Novel 1,3-dihydro-2h-benzimidazol-2-one derivatives substituted with heterocycles as respiratory syncytial virus antiviral agents

ABSTRACT

The present invention is concerned with novel 1,3-dihydro-2H-benzimidazol-2-one derivatives substituted with heterocycles having formula (I) 
     
       
         
         
             
             
         
       
     
     stereoisomeric forms thereof, and the pharmaceutically acceptable addition salts, and the solvates thereof,
 
wherein R 4 , R 5 , Z and Het have the meaning defined in the claims. The compounds according to the present invention are useful as inhibitors on the replication of the respiratory syncytial virus (RSV). The invention further concerns the preparation of such novel compounds, compositions comprising these compounds, and the compounds for use in the treatment of respiratory syncytial virus infection.

FIELD OF THE INVENTION

The invention concerns novel 1,3-dihydro-2H-benzimidazol-2-onederivatives substituted with heterocycles having antiviral activity, inparticular, having an inhibitory activity on the replication of therespiratory syncytial virus (RSV). The invention further concerns thepreparation of such novel compounds, compositions comprising thesecompounds, and the compounds for use in the treatment of respiratorysyncytial virus infection.

BACKGROUND

Human RSV or Respiratory Syncytial Virus is a large RNA virus, member ofthe family of Paramyxoviridae, subfamily pneumoviridae together withbovine RSV virus. Human RSV is responsible for a spectrum of respiratorytract diseases in people of all ages throughout the world. It is themajor cause of lower respiratory tract illness during infancy andchildhood. Over half of all infants encounter RSV in their first year oflife, and almost all within their first two years. The infection inyoung children can cause lung damage that persists for years and maycontribute to chronic lung disease in later life (chronic wheezing,asthma). Older children and adults often suffer from a (bad) common coldupon RSV infection. In old age, susceptibility again increases, and RSVhas been implicated in a number of outbreaks of pneumonia in the agedresulting in significant mortality.

Infection with a virus from a given subgroup does not protect against asubsequent infection with an RSV isolate from the same subgroup in thefollowing winter season. Re-infection with RSV is thus common, despitethe existence of only two subtypes, A and B.

Today only three drugs have been approved for use against RSV infection.A first one is ribavirin, a nucleoside analogue that provides an aerosoltreatment for serious RSV infection in hospitalized children. Theaerosol route of administration, the toxicity (risk of teratogenicity),the cost and the highly variable efficacy limit its use. The other twodrugs, RespiGam® (RSV-IG) and Synagis® (palivizumab), polyclonal andmonoclonal antibody immunostimulants, are intended to be used in apreventive way. Both are very expensive, and require parenteraladministration.

Other attempts to develop a safe and effective RSV vaccine have all metwith failure thus far. Inactivated vaccines failed to protect againstdisease, and in fact in some cases enhanced disease during subsequentinfection. Life attenuated vaccines have been tried with limitedsuccess. Clearly there is a need for an efficacious non-toxic and easyto administer drug against RSV replication. It would be particularlypreferred to provide drugs against RSV replication that could beadministered perorally.

A reference on benzimidazole antiviral agents is WO-01/95910. Hereincompounds are presented to have antiviral activity, yet with EC₅₀ valuesover a wide range of from 0.001 μm to as high as 50 μM (which does notnormally represent the desired biological activity). Another reference,relating to substituted 2-methyl-benzimidazole RSV antiviral agents, inthe same range of activities is WO-03/053344. Another related backgroundreference on compounds in the same range of activities, is WO-02/26228regarding benzimidazolone antiviral agents. A reference onstructure-activity relations, in respect of RSV inhibition, of5-substituted benzimidazole compounds is Kuo-Long Yu et al., Bioorganicand Medicinal Chemistry Letters 14 (2004) 1133-1137, Kuo-Long Yu et al.,Bioorganic and Medicinal Chemistry Letters 17 (2007) 895-901, and X. A.Wang et al., Bioorganic and Medicinal Chemistry Letters 17 (2007)4592-4598.

WO-2004/069256 discloses 2-cyanopyrrolopyrimidines as capthepsin K or Sinhibitors useful in the treatment of various pain disorders.WO-2008/147697 discloses benzimidazole derivatives as chymaseinhibitors.

WO-2012/080446, WO-2012/080447, WO-2012/080449, WO-2012/080450 andWO-2012/080481 all filed on 16 Dec. 2011 and published on 21 Jun. 2012disclose benzimidazole derivatives having antiviral activity againstrespiratory syncytial virus.

It is desired to provide new drugs that have antiviral activity.Particularly, it would be desired to provide new drugs that have RSVreplication inhibitory activity. Further, it would be desired toretrieve compound structures that allow obtaining antiviral biologicalactivities of the order of magnitude in the stronger regions of theprior art (i.e. at the bottom of the above-mentioned range of up to 50μM), and preferably at a level of about the most active, more preferablyof even stronger activity, than the compounds disclosed in the art. Afurther desire is to find compounds having oral antiviral activity.

SUMMARY OF THE INVENTION

In order to better address one or more of the foregoing desires, theinvention, in one aspect, presents antiviral compounds represented byformula (I),

and stereoisomeric forms thereof, whereinHet is a heterocycle having formula (b), (c), (d) or (e)

each X independently is C or N; provided that at least one X is N;

-   R^(1b) is present when Het has formula (b) and X is C; each R^(1b)    is selected independently from the group consisting of H, halogen,    C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, N(R⁶)₂, CO(R⁷), CH₂NH₂,    CH₂OH, CN, C(═NOH)NH₂, C(═NOCH₃)NH₂, C(═NH)NH₂, CF₃, OCF₃, B(OH)₂    and B(O—C₁-C₆alkyl)₂; R^(1b) is absent when the X to which it is    bound is N;-   R^(2b) is —(CR⁸R⁹)_(m)—R^(10b);-   each R⁶ is independently selected from the group consisting of H,    C₁-C₆alkyl, COOCH₃ and CONHSO₂CH₃;-   each R⁷ is independently selected from the group consisting of OH,    C₁-C₆alkyloxy, NH₂, NHSO₂N(C₁-C₆alkyl)₂, NHSO₂NHCH₃,    NHSO₂(C₁-C₆alkyl), NHSO₂(C₃-C₇cycloalkyl) and N(C₁-C₆-alkyl)₂;-   each R⁸ and R⁹ are independently chosen from the group consisting of    H, C₁-C₁₀alkyl and C₃-C₇cycloalkyl; or R⁸ and R⁹ taken together form    a 4 to 6 membered aliphatic ring that optionally contains one or    more heteroatoms selected from the group consisting of N, S and O;-   R^(10b) is selected from the group consisting of H, R¹¹, OH, CN, F,    CF₂H, CF₃, CONR⁸R⁹, COOR⁸, CON(R⁸)SO₂R⁹, CON(R⁸)SO₂N(R⁸R⁹), NR⁸R⁹,    NR⁸COOR⁹, OCOR⁸, O-Benzyl, NR⁸SO₂R⁹, SO₂NR⁸R⁹, SO₂R⁸, OCONR⁸R⁹,    OCONR⁸R¹², N(R⁸)CON(R⁸R⁹), N(R⁸)COOR¹², and a 4 to 6 membered    saturated ring containing one oxygen atom;-   m is an integer from 2 to 6;-   R¹¹ is selected from the group consisting of C₁-C₆ alkyl,    C₃-C₇cycloalkyl, phenyl, pyridinyl and pyrazolyl; each optionally    substituted with one or more substituents each independently    selected from the group consisting of CF₃, CH₃, OCH₃, OCF₃ and    halogen;-   R¹² is selected from the group consisting of phenyl, pyridinyl and    pyrazolyl; each optionally substituted with one or more substituents    each independently selected from the group consisting of CF₃, CH₃,    OCH₃, OCF₃ and halogen;    -    or R¹² is C₁-C₆ alkyl or C₃-C₇cycloalkyl; each substituted with        one or more substituents each independently selected from the        group consisting of CF₃, CH₃, OCH₃, OCF₃ and halogen;-   R^(1c) is present when Het has formula (c);-   each R^(1c) is selected independently from the group consisting of    H, halogen, C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, N(R⁶)₂,    CO(R^(7c)), CH₂NH₂, CH₂OH, CN, C(═NOH)NH₂, C(═NOCH₃)NH₂, C(═NH)NH₂,    CF₃, OCF₃, B(OH)₂ and B(O—C₁-C₆alkyl)₂;-   R^(3c) is selected from the group consisting of H, halogen,    C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy and CO(R^(7c));-   R^(2c) is (CR⁸R⁹)_(m)—R^(10c);-   R^(7c) is selected from the group consisting of OH, O(C₁-C₆alkyl),    NH₂, NHSO₂N(C₁-C₆alkyl)₂, NHSO₂NHCH₃, NHSO₂(C₁-C₆alkyl),    NHSO₂(C₃-C₇cycloalkyl), N(C₁-C₆-alkyl)₂, NR⁸R⁹ and NR⁹R^(10c);-   R^(10c) is selected from the group consisting of H, R¹¹, OH, CN, F,    CF₂H, CF₃, C(═NOH)NH₂, CONR⁸R⁹, COOR⁸, CONR⁸SO₂R⁹,    CON(R⁸)SO₂N(R⁸R⁹), NR⁸R⁹, NR⁸COOR⁹, OCOR⁸, NR⁸SO₂R⁹, SO₂NR⁸R⁹, SO₂R⁸    and a 4 to 6 membered saturated ring containing one oxygen atom;-   R^(1d) is present when Het has formula (d) and X is C; each R^(1d)    is selected independently from the group consisting of H, OH,    halogen, C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, N(R⁶)₂, CO(R⁷),    CH₂NH₂, CH₂OH, C(═NOH)NH₂, C(═NOCH₃)NH₂, C(═NH)NH₂, CF₃, OCF₃,    B(OH)₂ and B(O—C₁-C₆alkyl)₂; R^(1d) is absent when the X to which it    is bound is N;-   R^(3d) is selected from the group consisting of H, halogen,    C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, and CO(R⁷);-   R^(2d) is —(CR⁸R⁹)_(m)—R^(10d);-   R^(10d) is selected from the group consisting of H, R¹¹, OH, CN, F,    CF₂H, CF₃, CONR⁸R⁹, COOR⁸, CONR⁸SO₂R⁹, CON(R⁸)SO₂N(R⁸R⁹), NR⁸R⁹,    NR⁸COOR₉, OCOR⁸, NR⁸SO₂R⁹, SO₂NR⁸R⁹, SO₂R⁸ and a 4 to 6 membered    saturated ring containing one oxygen atom;-   each Y independently is C or N;-   R^(1e) is present when Het has formula (e) and Y is C; each R^(1e)    is selected independently from the group consisting of H, halogen,    C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, N(R⁶)₂, CO(R⁷), CH₂NH₂,    CH₂OH, CN, C(═NOH)NH₂, C(═NOCH₃)NH₂, C(═NH)NH₂, CF₃, OCF₃, B(OH)₂    and B(O—C₁-C₆alkyl)₂; R^(1e) is absent when the Y to which it is    bound is N;-   R^(3e) is selected from the group consisting of H, halogen,    —(CR⁸R⁹)_(m)—R^(10e), C≡C—CH₂—R^(10e), C≡C—R^(10e) and C═C—R^(10e);-   R^(10e) is selected from the group consisting of H, R¹¹,    C₁-C₆alkyloxy, OH, CN, F, CF₂H, CF₃, CONR⁸R⁹, COOR⁸, CON(R⁸)SO₂R⁹,    CON(R⁸)SO₂N(R⁸R⁹), NR⁸R⁹, NR⁸COOR⁹, OCOR⁸, NR⁸SO₂R⁹, SO₂NR⁸R⁹, SO₂R⁸    and a 4 to 6 membered saturated ring containing one oxygen atom;-   R⁴ is selected from the group consisting of tert-butyl, Het¹, aryl,    Het², CH(CH₃)(CF₃), and C₃-C₇cycloalkyl substituted with one or more    substituents selected from the group consisting of halo and    C₁-C₄alkyl;-   aryl represents phenyl or naphthalenyl; said aryl optionally being    substituted with one or more substituents each independently    selected from the group consisting of halo, C₁-C₄alkyloxy,    C₁-C₄alkyl, OH, CN, CF₂H, CF₃, CF₃O, CONR⁸R⁹, COOR⁸, CON(R⁸)SO₂R⁹,    CON(R⁸)SO₂N(R⁸R⁹), NR⁸R⁹, NR⁸COOR⁹, OCOR⁸, NR⁸SO₂R⁹, SO₂NR⁸R⁹,    SO₂R⁸, OCONR⁸R⁹, OCONR⁸R¹², N(R⁸)CON(R⁸R⁹), N(R⁸)COOR¹², or    C₁₋₄alkyloxy, C₁₋₄alkyloxy;

Het¹ represents a 4 to 6 membered saturated ring containing one N atom,optionally being substituted with one or more substituents eachindependently selected from the group consisting of halo, C₁-C₄alkyloxy,SO₂R⁸, C₁-C₄alkylcarbonyl, CO(aryl), COHet², C₁-C₄alkyloxycarbonyl,pyridinyl, CF₃, SO₂N(C₁-C₄alkyl)₂, SO₂NH(C₁-C₄alkyl),(C═O)NH(C₁₋₄alkyl), (C═S)NH(C₁₋₄alkyl), C₁-C₄alkyl and C₁-C₄alkylsubstituted with one hydroxy; or

-   -    Het¹ represents a 4 to 6 membered saturated ring containing one        O atom, substituted with one or more substituents each        independently selected from the group consisting of halo,        C₁-C₄alkyloxy, CF₃, NH(C═O)(C₁₋₄alkyl), (C═O)NH(C₁₋₄alkyl) and        C₁-C₄alkyl; or    -    Het¹ represents a bicyclic 7 to 11 membered non-aromatic        heterocycle containing one or two heteroatoms each independently        selected from the group consisting of O, S and N, optionally        substituted with one or more substituents each independently        selected from the group consisting of halo, C₁-C₄alkyloxy,        SO₂R⁸, C₁-C₄alkylcarbonyl, CO(aryl), COHet²,        C₁-C₄alkyloxycarbonyl, pyridinyl, CF₃, SO₂N(C₁-C₄alkyl)₂,        SO₂NH(C₁-C₄alkyl), (C═O)NH(C₁₋₄alkyl), (C═S)NH(C₁₋₄alkyl),        C₁-C₄alkyl and C₁-C₄alkyl substituted with one hydroxy;

-   Het² represents a monocyclic 5 to 6 membered aromatic heterocycle    containing one or more heteroatoms each independently selected from    the group consisting of O, S and N; or a bicyclic 8 to 12 membered    aromatic heterocycle containing one or more heteroatoms each    independently selected from the group consisting of O, S and N; said    Het² optionally being substituted with one or more substituents each    independently selected from the group consisting of halo,    C₁-C₄alkyloxy, C₁-C₄alkyl, OH, CN, CF₂H, CF₃, CONR⁸R⁹, COOR⁸,    CON(R⁸)SO₂R⁹, CON(R⁸)SO₂N(R⁸R⁹), NR⁸R⁹, NR⁸COOR⁹, OCOR⁸, NR⁸SO₂R⁹,    SO₂NR⁸R⁹, SO₂R⁸, OCONR⁸R⁹, OCONR⁸R¹², N(R⁸)CON(R⁸R⁹), N(R⁸)COOR¹²;

-   Z is C or N; R⁵ is present where Z is C, whereby R⁵ is selected form    the group consisting of hydrogen, CF₃ and halogen; R⁵ is absent    where Z is N;    and the pharmaceutically acceptable addition salts, and the solvates    thereof.

In another aspect, the invention relates to the foregoing compounds foruse in the treatment of RSV infections in warm-blooded animals,preferably humans. In yet another aspect, the invention presents amethod of treatment of viral RSV infections in a subject in needthereof, comprising administering to said subject an effective amount ofa compound as defined above. In still another aspect, the inventionresides in the use of a compound as defined above, for the manufactureof a medicament in the treatment of RSV infections.

In a further aspect, the invention relates to a pharmaceuticalcomposition comprising a compound as defined above, and apharmaceutically acceptable excipient.

In a still further aspect, the invention provides methods for preparingthe compounds defined above.

DETAILED DESCRIPTION OF THE INVENTION

The invention, in a broad sense, is based on the judicious recognitionthat the compounds of Formula (I) generally possess an interesting RSVinhibitory activity. Moreover, these compounds enable access to anti-RSVactivities at the higher regions (lower end of the EC₅₀ values) of therange available in the aforementioned references. Particularly, on thebasis of these compounds, molecular structures can be uncovered thateven outperform the reference compounds in terms of biologicalactivities.

The present invention will further be described with respect toparticular embodiments and with reference to certain examples but theinvention is not limited thereto but only by the claims. Where the term“comprising” is used in the present description and claims, it does notexclude other elements or steps. Where an indefinite or definite articleis used when referring to a singular noun e.g. “a” or “an”, “the”, thisincludes a plural of that noun unless something else is specificallystated.

Whenever the term “substituted” is used in the present invention, it ismeant, unless otherwise is indicated or is clear from the context, toindicate that one or more hydrogens, in particular from 1 to 4hydrogens, preferably from 1 to 3 hydrogens, more preferably 1 hydrogen,on the atom or radical indicated in the expression using “substituted”are replaced with a selection from the indicated group, provided thatthe normal valency is not exceeded, and that the substitution results ina chemically stable compound, i.e. a compound that is sufficientlyrobust to survive isolation to a useful degree of purity from a reactionmixture, and formulation into a therapeutic agent.

As used herein “C₁-C₄alkyl” or “C₁₋₄alkyl” as a group or part of a groupdefines straight or branched chain saturated hydrocarbon radicals havingfrom 1 to 4 carbon atoms such as methyl, ethyl, propyl, 1-methylethyl,butyl and the like.

As used herein “C₁-C₆alkyl” as a group or part of a group definesstraight or branched chain saturated hydrocarbon radicals having from 1to 6 carbon atoms such as methyl, ethyl, propyl, 1-methylethyl, butyl,pentyl, hexyl, 2-methylbutyl and the like.

“C₁-C₁₀alkyl” as a group or part of a group defines straight or branchedchain saturated hydrocarbon radicals having from 1 to 10 carbon atomssuch as the groups defined for C₁-C₆alkyl and heptyl, octyl, nonyl,2-methylhexyl, 2-methylheptyl, decyl, 2-methylnonyl, and the like.

The term “C₂-C₁₀alkenyl” used herein as a group or part of a group ismeant to comprise straight or branched chain unsaturated hydrocarbonradicals having at least one double bond, and preferably having onedouble bond, and from 2 to 10 carbon atoms such as ethenyl, propenyl,buten-1-yl, buten-2-yl, penten-1-yl, penten-2-yl, hexen-1-yl,hexen-2-yl, hexen-3-yl, 2-methylbuten-1-yl, hepten-1-yl, hepten-2-yl,hepten-3-yl, hepten-4-yl, 2-methylhexen-1-yl, octen-1-yl, octen-2-yl,octen-3-yl, octen-4-yl, 2-methylhepten-1-yl, nonen-1-yl, nonen-2-yl,nonen-3-yl, nonen-4-yl, nonen-5-yl, 2-methylocten-1-yl, decen-1-yl,decen-2-yl, decen-3-yl, decen-4-yl, decen-5-yl, 2-methylnonen-1-yl, andthe like.

Whenever a “C₂-C₁₀alkenyl” group is linked to a heteroatom it preferablyis linked via a saturated carbon atom.

“C₁-C₄alkyloxy” or “C₁-C₄alkoxy”, as a group or part of a group definesan O—C₁-C₄alkyl radical, wherein C₁-C₄alkyl has, independently, themeaning given above.

“C₁-C₆alkyloxy” or “C₁-C₆alkoxy”, as a group or part of a group definesan O—C₁-C₆alkyl radical, wherein C₁-C₆alkyl has, independently, themeaning given above.

The term “C₃-C₇cycloalkyl” alone or in combination, refers to a cyclicsaturated hydrocarbon radical having from 3 to 7 carbon atoms.Non-limiting examples of suitable C₃-C₇cycloalkyl include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

The term “—(CR⁸R⁹)_(m)—” used herein defines m repetitions of the CR⁸R⁹subgroup, wherein each of these subgroups is independently defined.

The term “halo” or “halogen” as a group or part of a group is genericfor fluoro, chloro, bromo, iodo unless otherwise is indicated or isclear from the context.

A term of the form NRCOOR is identical to N(R)COOR.

Examples of (but not limited to) a 4 to 6 membered aliphatic ringoptionally containing one or more heteroatoms selected from the groupconsisting of N, S and O, as used in the definitions of R⁸ and R⁹, arecyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, oxetanyl,tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, azetidinyl,thiolanyl, piperazinyl, pyrrolidinyl.

An example of (but not limited to) Het² is thiazolyl or quinolinyl.

An example of (but not limited to) Het¹ is azetidinyl.

It should be noted that the radical positions on any molecular moietyused in the definitions may be anywhere on such moiety as long as it ischemically stable. Radicals used in the definitions of the variablesinclude all possible isomers unless otherwise indicated. For instancepentyl includes 1-pentyl, 2-pentyl and 3-pentyl.

When any variable occurs more than one time in any constituent, eachdefinition is independent.

Hereinbefore and hereinafter, the term “compound of formula (I)” or“compounds of formula (I)” is meant to include the stereoisomeric formsthereof, and the pharmaceutically acceptable addition salts, and thesolvates thereof.

The terms “stereoisomers”, “stereoisomeric forms” or “stereochemicallyisomeric forms” hereinbefore or hereinafter are used interchangeably.

The term “stereochemically isomeric forms” as used hereinbefore definesall the possible compounds made up of the same atoms bonded by the samesequence of bonds but having different three-dimensional structureswhich are not interchangeable, which the compounds of formula (I) maypossess.

It will be appreciated that some of the compounds of formula (I) maycontain one or more centers of chirality and exist as stereochemicallyisomeric forms.

The invention includes all stereoisomers of the compound of Formula (I),either as a pure stereoisomer or as a mixture of two or morestereoisomers.

Enantiomers are stereoisomers that are non-superimposable mirror imagesof each other. A 1:1 mixture of a pair of enantiomers is a racemate orracemic mixture. Diastereomers (or diastereoisomers) are stereoisomersthat are not enantiomers, i.e. they are not related as mirror images. Ifa compound contains a double bond, the substituents may be in the E orthe Z configuration. Substituents on bivalent cyclic (partially)saturated radicals may have either the cis- or trans-configuration; forexample if a compound contains a disubstituted cycloalkyl group, thesubstituents may be in the cis or trans configuration. Therefore, theinvention includes enantiomers, diastereomers, racemates, E isomers, Zisomers, cis isomers, trans isomers and mixtures thereof, wheneverchemically possible.

The absolute configuration is specified according to theCahn-Ingold-Prelog system. The configuration at an asymmetric atom isspecified by either R or S. Resolved compounds whose absoluteconfiguration is not known can be designated by (+) or (−) depending onthe direction in which they rotate plane polarized light.

When a specific stereoisomer is identified, this means that saidstereoisomer is substantially free, i.e. associated with less than 50%,preferably less than 20%, more preferably less than 10%, even morepreferably less than 5%, in particular less than 2% and most preferablyless than 1%, of the other isomers. Thus, when a compound of formula (I)is for instance specified as (R), this means that the compound issubstantially free of the (S) isomer; when a compound of formula (I) isfor instance specified as E, this means that the compound issubstantially free of the Z isomer; when a compound of formula (I) isfor instance specified as cis, this means that the compound issubstantially free of the trans isomer.

Some of the compounds according to formula (I) may also exist in theirtautomeric form. Such forms although not explicitly indicated in theabove formula are intended to be included within the scope of thepresent invention.

Unless otherwise mentioned or indicated, the chemical designation of acompound encompasses the mixture of all possible stereochemicallyisomeric forms which said compound may possess. Said mixture may containall diastereomers and/or enantiomers of the basic molecular structure ofsaid compound. All stereochemically isomeric forms of the compounds ofthe present invention both in pure form or in admixture with each otherare intended to be embraced within the scope of the present invention.

Pure stereoisomeric forms of the compounds and intermediates of thisinvention may be obtained by the application of art-known procedures.For instance, enantiomers may be separated from each other by theselective crystallization of their diastereomeric salts with opticallyactive acids or bases. Examples thereof are tartaric acid,dibenzoyl-tartaric acid, ditoluoyltartaric acid and camphosulfonic acid.Alternatively, enantiomers may be separated by chromatographictechniques using chiral stationary phases. Said pure stereochemicallyisomeric forms may also be derived from the corresponding purestereochemically isomeric forms of the appropriate starting materials,provided that the reaction occurs stereospecifically. Preferably, if aspecific stereoisomer is desired, said compound will be synthesized bystereospecific methods of preparation. These methods will advantageouslyemploy enantiomerically pure starting materials.

The diastereomeric racemates of formula (I) can be obtained separatelyby conventional methods. Appropriate physical separation methods thatmay advantageously be employed are, for example, selectivecrystallization and chromatography, e.g. column chromatography.

For some of the compounds of formula (I) and stereoisomeric formsthereof, and the pharmaceutically acceptable addition salts, and thesolvates thereof; and intermediates used in the preparation thereof, theabsolute stereochemical configuration was not experimentally determined.A person skilled in the art is able to determine the absoluteconfiguration of such compounds using art-known methods such as, forexample, X-ray diffraction.

The present invention is also intended to include all isotopes of atomsoccurring on the present compounds. Isotopes include those atoms havingthe same atomic number but different mass numbers. By way of generalexample and without limitation, isotopes of hydrogen include tritium anddeuterium. Isotopes of carbon include C-13 and C-14.

For therapeutic use, salts of the compounds of formula (I) are thosewherein the counterion is pharmaceutically acceptable. However, salts ofacids and bases which are non-pharmaceutically acceptable may also finduse, for example, in the preparation or purification of apharmaceutically acceptable compound. All salts, whetherpharmaceutically acceptable or not are included within the ambit of thepresent invention.

The pharmaceutically acceptable acid and base addition salts asmentioned hereinabove are meant to comprise the therapeutically activenon-toxic acid and base addition salt forms which the compounds offormula (I) are able to form. The pharmaceutically acceptable acidaddition salts can conveniently be obtained by treating the base formwith such appropriate acid. Appropriate acids comprise, for example,inorganic acids such as hydrohalic acids, e.g. hydrochloric orhydrobromic acid, sulfuric, nitric, phosphoric and the like acids; ororganic acids such as, for example, acetic, propanoic, hydroxyacetic,lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e.butane-dioic acid), maleic, fumaric, malic (i.e. hydroxybutanedioicacid), tartaric, citric, methanesulfonic, ethanesulfonic,benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic,p-aminosalicylic, pamoic and the like acids.

Conversely said salt forms can be converted by treatment with anappropriate base into the free base form.

The compounds of formula (I) containing an acidic proton may also beconverted into their non-toxic metal or amine addition salt forms bytreatment with appropriate organic and inorganic bases. Appropriate basesalt forms comprise, for example, the ammonium salts, the alkali andearth alkaline metal salts, e.g. the lithium, sodium, potassium,magnesium, calcium salts and the like, salts with organic bases, e.g.the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts withamino acids such as, for example, arginine, lysine and the like.

The term solvate comprises the hydrates and solvent addition forms whichthe compounds of Formula (I) are able to form, as well as the saltsthereof. Examples of such forms are e.g. hydrates, alcoholates and thelike.

It will be appreciated that the compounds of the invention, withreference to the aforementioned left- and right-hand parts of formula I,present a wide variety of modification.

Without detracting from the overall scope of the invention, certainembodiments are discussed in more detail below.

A compound according to the invention therefore inherently comprises acompound with one or more isotopes of one or more element, and mixturesthereof, including a radioactive compound, also called radiolabelledcompound, wherein one or more non-radioactive atoms has been replaced byone of its radioactive isotopes. By the term “radiolabelled compound” ismeant any compound according to Formula (I) which contains at least oneradioactive atom. For example, a compound can be labelled with positronor with gamma emitting radioactive isotopes. For radioligand-bindingtechniques, the ³H-atom or the ¹²⁵I-atom is the atom of choice to bereplaced. For imaging, the most commonly used positron emitting (PET)radioactive isotopes are ¹¹C, ¹⁸F, ¹⁵O and ¹³N, all of which areaccelerator produced and have half-lives of 20, 100, 2 and 10 minutes(min) respectively. Since the half-lives of these radioactive isotopesare so short, it is only feasible to use them at institutions which havean accelerator on site for their production, thus limiting their use.The most widely used of these are ¹⁸F, ^(99m)Tc, ²⁰¹Tl and ¹²³I. Thehandling of these radioactive isotopes, their production, isolation andincorporation in a molecule are known to the skilled person.

In particular, the radioactive atom is selected from the group ofhydrogen, carbon, nitrogen, sulfur, oxygen and halogen. In particular,the radioactive isotope is selected from the group of ³H, ¹¹C, ¹⁸F,¹²²I, ¹²³I, ¹²⁵I, ¹³¹I, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br and ⁸²Br.

The terms described above and others used in the specification are wellunderstood to those in the art.

Preferred features of the compounds of this invention are now set forth.

In an embodiment, the present invention concerns novel compounds ofFormula (I) and stereoisomeric forms thereof, wherein Het is aheterocycle having formula (b), (c), (d) or (e);

-   each X independently is C or N; provided that at least one X is N;-   R^(1b) is present when Het has formula (b) and X is C; each R^(1b)    is selected independently from the group consisting of H, halogen,    C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, N(R⁶)₂, CO(R⁷), CH₂NH₂,    CH₂OH, CN, C(═NOH)NH₂, C(═NOCH₃)NH₂, C(═NH)NH₂, CF₃, OCF₃, B(OH)₂    and B(O—C₁-C₆alkyl)₂; R^(1b) is absent when the X to which it is    bound is N;-   R^(2b) is —(CR⁸R⁹)_(m)—R^(10b),-   each R⁶ is independently selected from the group consisting of H,    C₁-C₆alkyl, COOCH₃ and CONHSO₂CH₃;-   each R⁷ is independently selected from the group consisting of OH,    C₁-C₆alkyloxy, NH₂, NHSO₂N(C₁-C₆alkyl)₂, NHSO₂NHCH₃,    NHSO₂(C₁-C₆alkyl), NHSO₂(C₃-C₇cycloalkyl) and N(C₁-C₆-alkyl)₂;-   each R⁸ and R⁹ are independently chosen from the group consisting of    H, C₁-C₁₀alkyl and C₃-C₇cycloalkyl; or R⁸ and R⁹ taken together form    a 4 to 6 membered aliphatic ring that optionally contains one or    more heteroatoms selected from the group consisting of N, S and O;-   R^(10b) is selected from the group consisting of H, R¹¹, OH, CN, F,    CF₂H, CF₃, CONR⁸R⁹, COOR⁸, CON(R⁸)SO₂R⁹, CON(R⁸)SO₂N(R⁸R⁹), NR⁸R⁹,    NR⁸COOR⁹, OCOR⁸, O-Benzyl, NR⁸SO₂R⁹, SO₂NR⁸R⁹, SO₂R⁸, OCONR⁸R⁹,    OCONR⁸R¹², N(R⁸)CON(R⁸R⁹), N(R⁸)COOR¹², and a 4 to 6 membered    saturated ring containing one oxygen atom;-   m is an integer from 2 to 6;-   R¹¹ is selected from the group consisting of C₁-C₆ alkyl,    C₃-C₇cycloalkyl, phenyl, pyridinyl and pyrazolyl; each optionally    substituted with one or more substituents each independently    selected from the group consisting of CF₃, CH₃, OCH₃, OCF₃ and    halogen;-   R¹² is selected from the group consisting of phenyl, pyridinyl and    pyrazolyl; each optionally substituted with one or more substituents    each independently selected from the group consisting of CF₃, CH₃,    OCH₃, OCF₃ and halogen; or R¹² is C₁-C₆ alkyl or C₃-C₇cycloalkyl;    each substituted with one or more substituents each independently    selected from the group consisting of CF₃, CH₃, OCH₃, OCF₃ and    halogen;-   R^(1c) is present when Het has formula (c);-   each R^(1c) is selected independently from the group consisting of    H, halogen, C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, N(R⁶)₂,    CO(R^(7c)), CH₂NH₂, CH₂OH, CN, C(═NOH)NH₂, C(═NOCH₃)NH₂, C(═NH)NH₂,    CF₃, OCF₃, B(OH)₂ and B(O—C₁-C₆alkyl)₂;-   R^(3c) is selected from the group consisting of H, halogen,    C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy and CO(R^(7c));-   R^(2c) is —(CR⁸R⁹)_(m)—R^(10c);-   R^(7c) is selected from the group consisting of OH, O(C₁-C₆alkyl),    NH₂, NHSO₂N(C₁-C₆alkyl)₂, NHSO₂NHCH₃, NHSO₂(C₁-C₆alkyl),    NHSO₂(C₃-C₇cycloalkyl), N(C₁-C₆-alkyl)₂, NR⁸R⁹ and NR⁹R^(10c);-   R^(10c) is selected from the group consisting of H, C₁-C₆alkyl, OH,    CN, F, CF₂H, CF₃, C(═NOH)NH₂, CONR⁸R⁹, COOR⁸, CONR⁸SO₂R⁹,    CON(R⁸)SO₂N(R⁸R⁹), NR⁸R⁹, NR⁸COOR⁹, OCOR⁸, NR⁸SO₂R⁹, SO₂NR⁸R⁹, SO₂R⁸    and a 4 to 6 membered saturated ring containing one oxygen atom;-   R^(1d) is present when Het has formula (d) and X is C; each R^(1d)    is selected independently from the group consisting of H, OH,    halogen, C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, N(R⁶)₂, CO(R⁷),    CH₂NH₂, CH₂OH, CN, C(═NOH)NH₂, C(═NOCH₃)NH₂, C(═NH)NH₂, CF₃, OCF₃,    B(OH)₂ and B(O—C₁-C₆alkyl)₂; R^(1d) is absent when the X to which it    is bound is N;-   R^(3d) is selected from the group consisting of H, halogen,    C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, and CO(R⁷);-   R^(2d) is —(CR⁸R⁹)_(m)—R^(10d);-   R^(10d) is selected from the group consisting of H, C₁-C₆alkyl, OH,    CN, F, CF₂H, CF₃, CONR⁸R⁹, COOR⁸, CONR⁸SO₂R⁹, CON(R⁸)SO₂N(R⁸R⁹),    NR⁸R⁹, NR⁸COOR₉, OCOR⁸, NR⁸SO₂R⁹, SO₂NR⁸R⁹, SO₂R⁸ and a 4 to 6    membered saturated ring containing one oxygen atom;-   each Y independently is C or N;-   R^(1e) is present when Het has formula (e) and Y is C; each R^(1e)    is selected independently from the group consisting of H, halogen,    C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, N(R⁶)₂, CO(R⁷), CH₂NH₂,    CH₂OH, CN, C(═NOH)NH₂, C(═NOCH₃)NH₂, C(═NH)NH₂, CF₃, OCF₃, B(OH)₂    and B(O—C₁-C₆alkyl)₂; R^(1e) is absent when the Y to which it is    bound is N;-   R^(3e) is selected from the group consisting of H, halogen,    —(CR⁸R⁹)_(m)—R^(10e) C≡C—CH₂—R^(10e), C≡C—R^(10e) and C═C—R^(10e);-   R^(10e) is selected from the group consisting of H, C₁-C₆alkyl,    C₁-C₆alkyloxy, C₃-C₇cycloalkyl, OH, CN, F, CF₂H, CF₃, CONR⁸R⁹,    COOR⁸, CON(R⁸)SO₂R⁹, CON(R⁸)SO₂N(R⁸R⁹), NR⁸R⁹, NR⁸COOR⁹, OCOR⁸,    NR⁸SO₂R⁹, SO₂NR⁸R⁹, SO₂R⁸ and a 4 to 6 membered saturated ring    containing one oxygen atom;-   R⁴ is selected from the group consisting of tert-butyl, Het¹, aryl,    Het², CH(CH₃)(CF₃), and C₃-C₇cycloalkyl substituted with one or more    substituents selected from the group consisting of halo and    C₁-C₄alkyl;-   aryl represents phenyl or naphthalenyl; said aryl optionally being    substituted with one or more substituents each independently    selected from the group consisting of halo, C₁-C₄alkyloxy,    C₁-C₄alkyl, OH, CN, CF₂H, CF₃, CONR⁸R⁹, COOR⁸, CON(R⁸)SO₂R⁹,    CON(R⁸)SO₂N(R⁸R⁹), NR⁸R⁹, NR⁸COOR⁹, OCOR⁸, NR⁸SO₂R⁹, SO₂NR⁸R⁹,    SO₂R⁸, OCONR⁸R⁹, OCONR⁸R¹², N(R⁸)CON(R⁸R⁹), N(R⁸)COOR¹²;-   Het¹ represents a 4 to 6 membered saturated ring containing one N    atom, optionally being substituted with one or more substituents    each independently selected from the group consisting of halo,    C₁-C₄alkyloxy, SO₂R⁸, C₁-C₄alkylcarbonyl, CO(aryl), COHet²,    C₁-C₄alkyloxycarbonyl, pyridinyl, CF₃, SO₂N(C₁-C₄alkyl)₂,    SO₂NH(C₁-C₄alkyl), (C═O)NH(C₁₋₄alkyl), (C═S)NH(C₁₋₄alkyl),    C₁-C₄alkyl and C₁-C₄alkyl substituted with one hydroxy; or    -    Het¹ represents a 4 to 6 membered saturated ring containing one        O atom, substituted with one or more substituents each        independently selected from the group consisting of halo,        C₁-C₄alkyloxy, CF₃, NH(C═O)(C₁₋₄alkyl), (C═O)NH(C₁₋₄alkyl) and        C₁-C₄alkyl; or    -    Het¹ represents a bicyclic 7 to 11 membered non-aromatic        heterocycle containing one or two heteroatoms each independently        selected from the group consisting of O, S and N, optionally        substituted with one or more substituents each independently        selected from the group consisting of halo, C₁-C₄alkyloxy,        SO₂R⁸, C₁-C₄alkylcarbonyl, CO(aryl), COHet²,        C₁-C₄alkyloxycarbonyl, pyridinyl, CF₃, SO₂N(C₁-C₄alkyl)₂,        SO₂NH(C₁-C₄alkyl), (C═O)NH(C₁₋₄alkyl), (C═S)NH(C₁₋₄alkyl),        C₁-C₄alkyl and C₁-C₄alkyl substituted with one hydroxy;-   Het² represents a monocyclic 5 to 6 membered aromatic heterocycle    containing one or more heteroatoms each independently selected from    the group consisting of O, S and N; or a bicyclic 8 to 12 membered    aromatic heterocycle containing one or more heteroatoms each    independently selected from the group consisting of O, S and N; said    Het² optionally being substituted with one or more substituents each    independently selected from the group consisting of halo,    C₁-C₄alkyloxy, C₁-C₄alkyl, OH, CN, CF₂H, CF₃, CONR⁸R⁹, COOR⁸,    CON(R⁸)SO₂R⁹, CON(R⁸)SO₂N(R⁸R⁹), NR⁸R⁹, NR⁸COOR⁹, OCOR⁸, NR⁸SO₂R⁹,    SO₂NR⁸R⁹, SO₂R⁸, OCONR⁸R⁹, OCONR⁸R¹², N(R⁸)CON(R⁸R⁹), N(R⁸)COOR¹²;-   Z is C or N; R⁵ is present where Z is C, whereby R⁵ is selected form    the group consisting of hydrogen, CF₃ and halogen; R⁵ is absent    where Z is N;    and the pharmaceutically acceptable addition salts, and the solvates    thereof.

In an embodiment, the present invention concerns novel compounds ofFormula (I) and stereoisomeric forms thereof, wherein Het is aheterocycle having formula (b), (c), (d) or (e);

-   each X independently is C or N; provided that at least one X is N;-   R^(1b) is present when Het has formula (b) and X is C; each R^(1b)    is selected independently from the group consisting of H, halogen,    C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, N(R⁶)₂, CO(R⁷), CH₂NH₂,    CH₂OH, CN, C(═NOH)NH₂, C(═NOCH₃)NH₂, C(═NH)NH₂, CF₃, OCF₃, B(OH)₂    and B(O—C₁-C₆alkyl)₂; R^(1b) is absent when the X to which it is    bound is N;-   R^(2b) is —(CR⁸R⁹)_(m)—R^(10b);-   each R⁶ is independently selected from the group consisting of H,    C₁-C₆alkyl, COOCH₃ and CONHSO₂CH₃;-   each R⁷ is independently selected from the group consisting of OH,    C₁-C₆alkyloxy, NH₂, NHSO₂N(C₁-C₆alkyl)₂, NHSO₂NHCH₃,    NHSO₂(C₁-C₆alkyl), NHSO₂(C₃-C₇cycloalkyl) and N(C₁-C₆-alkyl)₂;-   each R⁸ and R⁹ are independently chosen from the group consisting of    H, C₁-C₁₀alkyl and C₃-C₇cycloalkyl; or R⁸ and R⁹ taken together form    a 4 to 6 membered aliphatic ring that optionally contains one or    more heteroatoms selected from the group consisting of N, S and O;-   R^(10b) is selected from the group consisting of H, R¹¹, OH, CN, F,    CF₂H, CF₃, CONR⁸R⁹, COOR⁸, CON(R⁸)SO₂R⁹, CON(R⁸)SO₂N(R⁸R⁹), NR⁸R⁹,    NR⁸COOR⁹, OCOR⁸, O-Benzyl, NR⁸SO₂R⁹, SO₂NR⁸R⁹, SO₂R⁸, OCONR⁸R⁹,    OCONR⁸R¹², N(R⁸)CON(R⁸R⁹), N(R⁸)COOR¹², and a 4 to 6 membered    saturated ring containing one oxygen atom;-   m is an integer from 2 to 6;-   R¹¹ is selected from the group consisting of C₁-C₆ alkyl,    C₃-C₇cycloalkyl, phenyl, pyridinyl and pyrazolyl; each optionally    substituted with one or more substituents each independently    selected from the group consisting of CF₃, CH₃, OCH₃, OCF₃ and    halogen;-   R¹² is selected from the group consisting of phenyl, pyridinyl and    pyrazolyl; each optionally substituted with one or more substituents    each independently selected from the group consisting of CF₃, CH₃,    OCH₃, OCF₃ and halogen;    -    or R¹² is C₁-C₆ alkyl or C₃-C₇cycloalkyl; each substituted with        one or more substituents each independently selected from the        group consisting of CF₃, CH₃, OCH₃, OCF₃ and halogen;-   R^(1c) is present when Het has formula (c);-   each R^(1c) is selected independently from the group consisting of    H, halogen, C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, N(R⁶)₂,    CO(R^(7c)), CH₂NH₂, CH₂OH, CN, C(═NOH)NH₂, C(═NOCH₃)NH₂, C(═NH)NH₂,    CF₃, OCF₃, B(OH)₂ and B(O—C₁-C₆alkyl)₂;-   R^(3c) is selected from the group consisting of H, halogen,    C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy and CO(R^(7c));-   R^(2c) is —(CR⁸R⁹)_(m)—R^(10c);-   R^(7c) is selected from the group consisting of OH, O(C₁-C₆alkyl),    NH₂, NHSO₂N(C₁-C₆alkyl)₂, NHSO₂NHCH₃, NHSO₂(C₁-C₆alkyl),    NHSO₂(C₃-C₇cycloalkyl), N(C₁-C₆-alkyl)₂, NR⁸R⁹ and NR⁹R^(10c);-   R^(10c) is selected from the group consisting of H, C₁-C₆alkyl, OH,    CN, F, CF₂H, CF₃, C(═NOH)NH₂, CONR⁸R⁹, COOR⁸, CONR⁸SO₂R⁹,    CON(R⁸)SO₂N(R⁸R⁹), NR⁸R⁹, NR⁸COOR⁹, OCOR⁸, NR⁸SO₂R⁹, SO₂NR⁸R⁹, SO₂R⁸    and a 4 to 6 membered saturated ring containing one oxygen atom;-   R^(1d) is present when Het has formula (d) and X is C; each R^(1d)    is selected independently from the group consisting of H, OH,    halogen, C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, N(R⁶)₂, CO(R⁷),    CH₂NH₂, CH₂OH, CN, C(═NOH)NH₂, C(═NOCH₃)NH₂, C(═NH)NH₂, CF₃, OCF₃,    B(OH)₂ and B(O—C₁-C₆alkyl)₂; R^(1d) is absent when the X to which it    is bound is N;-   R^(3d) is selected from the group consisting of H, halogen,    C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, and CO(R⁷);-   R^(2d) is —(CR⁸R⁹)_(m)—R^(10d);-   R^(10d) is selected from the group consisting of H, C₁-C₆alkyl, OH,    CN, F, CF₂H, CF₃, CONR⁸R⁹, COOR⁸, CONR⁸SO₂R⁹, CON(R⁸)SO₂N(R⁸R⁹),    NR⁸R⁹, NR⁸COOR₉, OCOR⁸, NR⁸SO₂R⁹, SO₂NR⁸R⁹, SO₂R⁸ and a 4 to 6    membered saturated ring containing one oxygen atom;-   each Y independently is C or N;-   R^(1e) is present when Het has formula (e) and Y is C; each R^(1e)    is selected independently from the group consisting of H, halogen,    C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, N(R⁶)₂, CO(R⁷), CH₂NH₂,    CH₂OH, CN, C(═NOH)NH₂, C(═NOCH₃)NH₂, C(═NH)NH₂, CF₃, OCF₃, B(OH)₂    and B(O—C₁-C₆alkyl)₂; R^(1e) is absent when the Y to which it is    bound is N;-   R^(3e) is selected from the group consisting of H, halogen,    —(CR⁸R⁹)_(m)—R^(10e), C≡C—CH₂R^(10e), C≡C—R^(10e) and C═C—R^(10e);-   R^(10e) is selected from the group consisting of H, C₁-C₆alkyl,    C₁-C₆alkyloxy, C₃-C₇cycloalkyl, OH, CN, F, CF₂H, CF₃, CONR⁸R⁹,    COOR⁸, CON(R⁸)SO₂R⁹, CON(R⁸)SO₂N(R⁸R⁹), NR⁸R⁹, NR⁸COOR⁹, OCOR⁸,    NR⁸SO₂R⁹, SO₂NR⁸R⁹, SO₂R⁸ and a 4 to 6 membered saturated ring    containing one oxygen atom;-   R⁴ is selected from the group consisting of tert-butyl, Het¹, aryl,    Het², CH(CH₃)(CF₃), and C₃-C₇cycloalkyl substituted with one or more    substituents selected from the group consisting of halo and    C₁-C₄alkyl;-   aryl represents phenyl or naphthalenyl; said aryl optionally being    substituted with one or more substituents each independently    selected from the group consisting of halo, C₁-C₄alkyloxy,    C₁-C₄alkyl, OH, CN, CF₂H, CF₃, CONR⁸R⁹, COOR⁸, CON(R⁸)SO₂R⁹,    CON(R⁸)SO₂N(R⁸R⁹), NR⁸R⁹, NR⁸COOR⁹, OCOR⁸, NR⁸SO₂R⁹, SO₂NR⁸R⁹,    SO₂R⁸, OCONR⁸R⁹, OCONR⁸R¹², N(R⁸)CON(R⁸R⁹), N(R⁸)COOR¹²;-   Het¹ represents a 4 to 6 membered saturated ring containing one N    atom, optionally being substituted with one or more substituents    each independently selected from the group consisting of halo,    C₁-C₄alkyloxy, SO₂R⁸, C₁-C₄alkylcarbonyl, CO(aryl), COHet²,    C₁-C₄alkyloxycarbonyl, pyridinyl, CF₃, SO₂N(C₁-C₄alkyl)₂,    SO₂NH(C₁-C₄alkyl), (C═O)NH(C₁₋₄alkyl), (C═S)NH(C₁₋₄alkyl),    C₁-C₄alkyl and C₁-C₄alkyl substituted with one hydroxy; or-    Het¹ represents a 4 to 6 membered saturated ring containing one O    atom, substituted with one or more substituents each independently    selected from the group consisting of halo, C₁-C₄alkyloxy, CF₃,    NH(C═O)(C₁₋₄alkyl), (C═O)NH(C₁₋₄alkyl) and C₁-C₄alkyl;-   Het² represents a monocyclic 5 to 6 membered aromatic heterocycle    containing one or more heteroatoms each independently selected from    the group consisting of O, S and N; or a bicyclic 8 to 12 membered    aromatic heterocycle containing one or more heteroatoms each    independently selected from the group consisting of O, S and N; said    Het² optionally being substituted with one or more substituents each    independently selected from the group consisting of halo,    C₁-C₄alkyloxy, C₁-C₄alkyl, OH, CN, CF₂H, CF₃, CONR⁸R⁹, COOR⁸,    CON(R⁸)SO₂R⁹, CON(R⁸)SO₂N(R⁸R⁹), NR⁸R⁹, NR⁸COOR⁹, OCOR⁸, NR⁸SO₂R⁹,    SO₂NR⁸R⁹, SO₂R⁸, OCONR⁸R⁹, OCONR⁸R¹², N(R⁸)CON(R⁸R⁹), N(R⁸)COOR¹²;-   Z is C or N; R⁵ is present where Z is C, whereby R⁵ is selected form    the group consisting of hydrogen, CF₃ and halogen; R⁵ is absent    where Z is N;    and the pharmaceutically acceptable addition salts, and the solvates    thereof

In an embodiment, the present invention concerns novel compounds ofFormula (I) and stereoisomeric forms thereof, wherein Het is aheterocycle having formula (b), (c), (d) or (e);

-   each X independently is C or N; provided that at least one X is N;-   R^(1b) is present when Het has formula (b) and X is C; each R^(1b)    is selected independently from the group consisting of H, halogen,    C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, N(R⁶)₂, CO(R⁷), CH₂NH₂,    CH₂OH, CN, C(═NOH)NH₂, C(═NOCH₃)NH₂, C(═NH)NH₂, CF₃, OCF₃, B(OH)₂    and B(O—C₁-C₆alkyl)₂; R^(1b) is absent when the X to which it is    bound is N;-   R^(2b) is —(CR⁸R⁹)_(m)—R^(10b);-   each R⁶ is independently selected from the group consisting of H,    C₁-C₆alkyl, COOCH₃ and CONHSO₂CH₃;-   each R⁷ is independently selected from the group consisting of OH,    C₁-C₆alkyloxy, NH₂, NHSO₂N(C₁-C₆alkyl)₂, NHSO₂NHCH₃,    NHSO₂(C₁-C₆alkyl), NHSO₂(C₃-C₇cycloalkyl) and N(C₁-C₆-alkyl)₂;-   each R⁸ and R⁹ are independently chosen from the group consisting of    H, C₁-C₁₀alkyl and C₃-C₇cycloalkyl; or R⁸ and R⁹ taken together form    a 4 to 6 membered aliphatic ring that optionally contains one or    more heteroatoms selected from the group consisting of N, S and O;-   R^(10b) is selected from the group consisting of H, R¹¹, OH, CN, F,    CF₂H, CF₃, CONR⁸R⁹, COOR⁸, CON(R⁸)SO₂R⁹, CON(R⁸)SO₂N(R⁸R⁹), NR⁸R⁹,    NR⁸COOR⁹, OCOR⁸, O-Benzyl, NR⁸SO₂R⁹, SO₂NR⁸R⁹, SO₂R⁸, OCONR⁸R⁹,    OCONR⁸R¹², N(R⁸)CON(R⁸R⁹), N(R⁸)COOR¹², and a 4 to 6 membered    saturated ring containing one oxygen atom;-   m is an integer from 2 to 6;-   R¹¹ is selected from the group consisting of C₁-C₆ alkyl,    C₃-C₇cycloalkyl, phenyl, pyridinyl and pyrazolyl; each optionally    substituted with one or more substituents each independently    selected from the group consisting of CF₃, CH₃, OCH₃, OCF₃ and    halogen;-   R¹² is selected from the group consisting of phenyl, pyridinyl and    pyrazolyl; each optionally substituted with one or more substituents    each independently selected from the group consisting of CF₃, CH₃,    OCH₃, OCF₃ and halogen;-    or R¹² is C₁-C₆ alkyl or C₃-C₇cycloalkyl; each substituted with one    or more substituents each independently selected from the group    consisting of CF₃, CH₃, OCH₃, OCF₃ and halogen;-   R^(1c) is present when Het has formula (c);-   each R^(1c) is selected independently from the group consisting of    H, halogen, C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, N(R⁶)₂,    CO(R^(7c)), CH₂NH₂, CH₂OH, CN, C(═NOH)NH₂, C(═NOCH₃)NH₂, C(═NH)NH₂,    CF₃, OCF₃, B(OH)₂ and B(O—C₁-C₆alkyl)₂;-   R^(3c) is selected from the group consisting of H, halogen,    C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy and CO(R^(7c));-   R^(2c) is —(CR⁸R⁹)_(m)—R^(10e),-   R^(7c) is selected from the group consisting of OH, O(C₁-C₆alkyl),    NH₂, NHSO₂N(C₁-C₆alkyl)₂, NHSO₂NHCH₃, NHSO₂(C₁-C₆alkyl),    NHSO₂(C₃-C₇cycloalkyl), N(C₁-C₆-alkyl)₂, NR⁸R⁹ and NR⁹R^(10c);-   R^(10c) is selected from the group consisting of H, C₁-C₆alkyl, OH,    CN, F, CF₂H, CF₃, C(═NOH)NH₂, CONR⁸R⁹, COOR⁸, CONR⁸SO₂R⁹,    CON(R⁸)SO₂N(R⁸R⁹), NR⁸R⁹, NR⁸COOR⁹, OCOR⁸, NR⁸SO₂R⁹, SO₂NR⁸R⁹, SO₂R⁸    and a 4 to 6 membered saturated ring containing one oxygen atom;-   R^(1d) is present when Het has formula (d) and X is C; each R^(1d)    is selected independently from the group consisting of H, OH,    halogen, C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, N(R⁶)₂, CO(R⁷),    CH₂NH₂, CH₂OH, CN, C(═NOH)NH₂, C(═NOCH₃)NH₂, C(═NH)NH₂, CF₃, OCF₃,    B(OH)₂ and B(O—C₁-C₆alkyl)₂; R^(1d) is absent when the X to which it    is bound is N;-   R^(3d) is selected from the group consisting of H, halogen,    C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, and CO(R⁷);-   R^(2d) is —(CR⁸R⁹)_(m)—R^(10d);-   R^(10d) is selected from the group consisting of H, C₁-C₆alkyl, OH,    CN, F, CF₂H, CF₃, CONR⁸R⁹, COOR⁸, CONR⁸SO₂R⁹, CON(R⁸)SO₂N(R⁸R⁹),    NR⁸R⁹, NR⁸COOR₉, OCOR⁸, NR⁸SO₂R⁹, SO₂NR⁸R⁹, SO₂R⁸ and a 4 to 6    membered saturated ring containing one oxygen atom;-   each Y independently is C or N;-   R^(1e) is present when Het has formula (e) and Y is C; each R^(1e)    is selected independently from the group consisting of H, halogen,    C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, N(R⁶)₂, CO(R⁷), CH₂NH₂,    CH₂OH, CN, C(═NOH)NH₂, C(═NOCH₃)NH₂, C(═NH)NH₂, CF₃, OCF₃, B(OH)₂    and B(O—C₁-C₆alkyl)₂; R^(1e) is absent when the Y to which it is    bound is N;-   R^(3e) is selected from the group consisting of H, halogen,    —(CR⁸R⁹)_(m)—R^(10e), C≡C—CH₂—R^(10e), C≡C—R^(10e) and C═C—R^(10e);-   R^(10e) is selected from the group consisting of H, C₁-C₆alkyl,    C₁-C₆alkyloxy, C₃-C₇cycloalkyl, OH, CN, F, CF₂H, CF₃, CONR⁸R⁹,    COOR⁸, CON(R⁸)SO₂R⁹, CON(R⁸)SO₂N(R⁸R⁹), NR⁸R⁹, NR⁸COOR⁹, OCOR⁸,    NR⁸SO₂R⁹, SO₂NR⁸R⁹, SO₂R⁸ and a 4 to 6 membered saturated ring    containing one oxygen atom;-   R⁴ is selected from the group consisting of tert-butyl, Het¹, aryl,    Het², CH(CH₃)(CF₃), and C₃-C₇cycloalkyl substituted with one or more    substituents selected from the group consisting of halo and    C₁-C₄alkyl;-   aryl represents phenyl or naphthalenyl; said aryl optionally being    substituted with one or more substituents each independently    selected from the group consisting of halo, C₁-C₄alkyloxy,    C₁-C₄alkyl, OH, CN, CF₂H, CF₃, CONR⁸R⁹, COOR⁸, CON(R⁸)SO₂R⁹,    CON(R⁸)SO₂N(R⁸R⁹), NR⁸R⁹, NR⁸COOR⁹, OCOR⁸, NR⁸SO₂R⁹, SO₂NR⁸R⁹,    SO₂R⁸, OCONR⁸R⁹, OCONR⁸R¹², N(R⁸)CON(R⁸R⁹), N(R⁸)COOR¹²;-   Het¹ represents a 4 to 6 membered saturated ring containing one N    atom, optionally being substituted with one or more substituents    each independently selected from the group consisting of halo,    C₁-C₄alkyloxy, SO₂R⁸, C₁-C₄alkylcarbonyl, CO(aryl), COHet²,    C₁-C₄alkyloxycarbonyl, pyridinyl, CF₃, SO₂N(C₁-C₄alkyl)₂,    SO₂NH(C₁-C₄alkyl), (C═O)NH(C₁₋₄alkyl), (C═S)NH(C₁₋₄alkyl),    C₁-C₄alkyl and C₁-C₄alkyl substituted with one hydroxy; or-    Het¹ represents a 4 to 6 membered saturated ring containing one O    atom, substituted with one or more substituents each independently    selected from the group consisting of halo, C₁-C₄alkyloxy, CF₃,    NH(C═O)(C₁₋₄alkyl), (C═O)NH(C₁₋₄alkyl) and C₁-C₄alkyl;-   Het² represents a monocyclic 5 to 6 membered aromatic heterocycle    containing one or more heteroatoms each independently selected from    the group consisting of O, S and N; or a bicyclic 8 to 12 membered    aromatic heterocycle containing one or more heteroatoms each    independently selected from the group consisting of O, S and N; said    Het² optionally being substituted with one or more substituents each    independently selected from the group consisting of halo,    C₁-C₄alkyloxy, C₁-C₄alkyl, OH, CN, CF₂H, CF₃, CONR⁸R⁹, COOR⁸,    CON(R⁸)SO₂R⁹, CON(R⁸)SO₂N(R⁸R⁹), NR⁸R⁹, NR⁸COOR⁹, OCOR⁸, NR⁸SO₂R⁹,    SO₂NR⁸R⁹, SO₂R⁸, OCONR⁸R⁹, OCONR⁸R¹², N(R⁸)CON(R⁸R⁹), N(R⁸)COOR¹²;-   Z is C or N; R⁵ is present where Z is C, whereby R⁵ is selected form    the group consisting of CF₃ and halogen; R⁵ is absent where Z is N;    and the pharmaceutically acceptable addition salts, and the solvates    thereof.

In an embodiment, the present invention concerns novel compounds ofFormula (I) and stereoisomeric forms thereof, wherein Het is aheterocycle having formula (b), (c), (d) or (e);

-   each X independently is C or N; provided that at least one X is N;-   R^(1b) is present when Het has formula (b) and X is C; each R^(1b)    is selected independently from the group consisting of H, halogen,    C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, N(R⁶)₂, CO(R⁷), CH₂NH₂,    CH₂OH, CN, C(═NOH)NH₂, C(═NOCH₃)NH₂, C(═NH)NH₂, CF₃, OCF₃, B(OH)₂    and B(O—C₁-C₆alkyl)₂; R^(1b) is absent when the X to which it is    bound is N;-   R^(2b) is —(CR⁸R⁹)_(m)—R^(10b);-   each R⁶ is independently selected from the group consisting of H,    C₁-C₆alkyl, COOCH₃ and CONHSO₂CH₃;-   each R⁷ is independently selected from the group consisting of OH,    C₁-C₆alkyloxy, NH₂, NHSO₂N(C₁-C₆alkyl)₂, NHSO₂NHCH₃,    NHSO₂(C₁-C₆alkyl), NHSO₂(C₃-C₇cycloalkyl) and N(C₁-C₆-alkyl)₂;-   each R⁸ and R⁹ are independently chosen from the group consisting of    H, C₁-C₁₀alkyl and C₃-C₇cycloalkyl; or R⁸ and R⁹ taken together form    a 4 to 6 membered aliphatic ring that optionally contains one or    more heteroatoms selected from the group consisting of N, S and O;-   R^(10b) is selected from the group consisting of H, R¹¹, OH, CN, F,    CF₂H, CF₃, CONR⁸R⁹, COOR⁸, CON(R⁸)SO₂R⁹, CON(R⁸)SO₂N(R⁸R⁹), NR⁸R⁹,    NR⁸COOR⁹, OCOR⁸, O-Benzyl, NR⁸SO₂R⁹, SO₂NR⁸R⁹, SO₂R⁸, OCONR⁸R⁹,    OCONR⁸R¹², N(R⁸)CON(R⁸R⁹), N(R⁸)COOR¹², and a 4 to 6 membered    saturated ring containing one oxygen atom;-   m is an integer from 2 to 6;-   R¹¹ is selected from the group consisting of C₁-C₆ alkyl,    C₃-C₇cycloalkyl, phenyl, pyridinyl and pyrazolyl; each optionally    substituted with one or more substituents each independently    selected from the group consisting of CF₃, CH₃, OCH₃, OCF₃ and    halogen;-   R¹² is selected from the group consisting of phenyl, pyridinyl and    pyrazolyl; each optionally substituted with one or more substituents    each independently selected from the group consisting of CF₃, CH₃,    OCH₃, OCF₃ and halogen;-    or R¹² is C₁-C₆ alkyl or C₃-C₇cycloalkyl; each substituted with one    or more substituents each independently selected from the group    consisting of CF₃, CH₃, OCH₃, OCF₃ and halogen;-   R^(1c) is present when Het has formula (c);-   each R^(1c) is selected independently from the group consisting of    H, halogen, C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, N(R⁶)₂,    CO(R^(7c)), CH₂NH₂, CH₂OH, CN, C(═NOH)NH₂, C(═NOCH₃)NH₂, C(═NH)NH₂,    CF₃, OCF₃, B(OH)₂ and B(O—C₁-C₆alkyl)₂;-   R^(3c) is selected from the group consisting of H, halogen,    C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy and CO(R^(7c));-   R^(2c) is —(CR⁸R⁹)_(m)—R^(10c);-   R^(7c) is selected from the group consisting of OH, O(C₁-C₆alkyl),    NH₂, NHSO₂N(C₁-C₆alkyl)₂, NHSO₂NHCH₃, NHSO₂(C₁-C₆alkyl),    NHSO₂(C₃-C₇cycloalkyl), N(C₁-C₆-alkyl)₂, NR⁸R⁹ and NR⁹R^(10c);-   R^(10c) is selected from the group consisting of H, C₁-C₆alkyl, OH,    CN, F, CF₂H, CF₃, C(═NOH)NH₂, CONR⁸R⁹, COOR⁸, CONR⁸SO₂R⁹,    CON(R⁸)SO₂N(R⁸R⁹), NR⁸R⁹, NR⁸COOR⁹, OCOR⁸, NR⁸SO₂R⁹, SO₂NR⁸R⁹, SO₂R⁸    and a 4 to 6 membered saturated ring containing one oxygen atom;-   R^(1d) is present when Het has formula (d) and X is C; each R^(1d)    is selected independently from the group consisting of H, OH,    halogen, C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, N(R⁶)₂, CO(R⁷),    CH₂NH₂, CH₂OH, CN, C(═NOH)NH₂, C(═NOCH₃)NH₂, C(═NH)NH₂, CF₃, OCF₃,    B(OH)₂ and B(O—C₁-C₆alkyl)₂; R^(1d) is absent when the X to which it    is bound is N;-   R^(3d) is selected from the group consisting of H, halogen,    C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, and CO(R⁷);-   R^(3d) is —(CR⁸R⁹)_(m)—R^(10d);-   R^(10d) is selected from the group consisting of H, C₁-C₆alkyl, OH,    CN, F, CF₂H, CF₃, CONR⁸R⁹, COOR⁸, CONR⁸SO₂R⁹, CON(R⁸)SO₂N(R⁸R⁹),    NR⁸R⁹, NR⁸COOR₉, OCOR⁸, NR⁸SO₂R⁹, SO₂NR⁸R⁹, SO₂R⁸ and a 4 to 6    membered saturated ring containing one oxygen atom;-   each Y independently is C or N;-   R^(1e) is present when Het has formula (e) and Y is C; each R^(1e)    is selected independently from the group consisting of H, halogen,    C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, N(R⁶)₂, CO(R⁷), CH₂NH₂,    CH₂OH, CN, C(═NOH)NH₂, C(═NOCH₃)NH₂, C(═NH)NH₂, CF₃, OCF₃, B(OH)₂    and B(O—C₁-C₆alkyl)₂; R^(1e) is absent when the Y to which it is    bound is N;-   R^(3e) is selected from the group consisting of H, halogen,    —(CR⁸R⁹)_(m)—R^(10e), C≡C—CH₂—R^(10e), C≡C—R^(10e) and C═C—R^(10e);-   R^(10e) is selected from the group consisting of H, C₁-C₆alkyl,    C₁-C₆alkyloxy, C₃-C₇cycloalkyl, OH, CN, F, CF₂H, CF₃, CONR⁸R⁹,    COOR⁸, CON(R⁸)SO₂R⁹, CON(R⁸)SO₂N(R⁸R⁹), NR⁸R⁹, NR⁸COOR⁹, OCOR⁸,    NR⁸SO₂R⁹, SO₂NR⁸R⁹, SO₂R⁸ and a 4 to 6 membered saturated ring    containing one oxygen atom;-   R⁴ is Het¹;-   aryl represents phenyl or naphthalenyl; said aryl optionally being    substituted with one or more substituents each independently    selected from the group consisting of halo, C₁-C₄alkyloxy,    C₁-C₄alkyl, OH, CN, CF₂H, CF₃, CONR⁸R⁹, COOR⁸, CON(R⁸)SO₂R⁹,    CON(R⁸)SO₂N(R⁸R⁹), NR⁸R⁹, NR⁸COOR⁹, OCOR⁸, NR⁸SO₂R⁹, SO₂NR⁸R⁹,    SO₂R⁸, OCONR⁸R⁹, OCONR⁸R¹², N(R⁸)CON(R⁸R⁹), N(R⁸)COOR¹²;-   Het¹ represents a 4 to 6 membered saturated ring containing one N    atom, optionally being substituted with one or more substituents    each independently selected from the group consisting of halo,    C₁-C₄alkyloxy, SO₂R⁸, C₁-C₄alkylcarbonyl, CO(aryl), COHet²,    C₁-C₄alkyloxycarbonyl, pyridinyl, CF₃, SO₂N(C₁-C₄alkyl)₂,    SO₂NH(C₁-C₄alkyl), (C═O)NH(C₁₋₄alkyl), (C═S)NH(C₁₋₄alkyl),    C₁-C₄alkyl and C₁-C₄alkyl substituted with one hydroxy; or-    Het¹ represents a 4 to 6 membered saturated ring containing one O    atom, substituted with one or more substituents each independently    selected from the group consisting of halo, C₁-C₄alkyloxy, CF₃,    NH(C═O)(C₁₋₄alkyl), (C═O)NH(C₁₋₄alkyl) and C₁-C₄alkyl;-   Het² represents a monocyclic 5 to 6 membered aromatic heterocycle    containing one or more heteroatoms each independently selected from    the group consisting of O, S and N; or a bicyclic 8 to 12 membered    aromatic heterocycle containing one or more heteroatoms each    independently selected from the group consisting of O, S and N; said    Het² optionally being substituted with one or more substituents each    independently selected from the group consisting of halo,    C₁-C₄alkyloxy, C₁-C₄alkyl, OH, CN, CF₂H, CF₃, CONR⁸R⁹, COOR⁸,    CON(R⁸)SO₂R⁹, CON(R⁸)SO₂N(R⁸R⁹), NR⁸R⁹, NR⁸COOR⁹, OCOR⁸, NR⁸SO₂R⁹,    SO₂NR⁸R⁹, SO₂R⁸, OCONR⁸R⁹, OCONR⁸R¹², N(R⁸)CON(R⁸R⁹), N(R⁸)COOR¹²;-   Z is C or N; R⁵ is present where Z is C, whereby R⁵ is selected form    the group consisting of hydrogen, CF₃ and halogen; R⁵ is absent    where Z is N;    and the pharmaceutically acceptable addition salts, and the solvates    thereof.

In an embodiment, the present invention concerns novel compounds ofFormula (I) and stereoisomeric forms thereof, wherein Het is aheterocycle having formula (b), (c), (d) or (e);

-   each X independently is C or N; provided that at least one X is N;-   R^(1b) is present when Het has formula (b) and X is C; each R^(1b)    is selected independently from the group consisting of H, halogen,    C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, N(R⁶)₂, CO(R⁷), CH₂NH₂,    CH₂OH, CN, C(═NOH)NH₂, C(═NOCH₃)NH₂, C(═NH)NH₂, CF₃, OCF₃, B(OH)₂    and B(O—C₁-C₆alkyl)₂; R^(1b) is absent when the X to which it is    bound is N;-   R^(2b) is —(CR⁸R⁹)_(m)—R^(10b);-   each R⁶ is independently selected from the group consisting of H,    C₁-C₆alkyl, COOCH₃ and CONHSO₂CH₃;-   each R⁷ is independently selected from the group consisting of OH,    C₁-C₆alkyloxy, NH₂, NHSO₂N(C₁-C₆alkyl)₂, NHSO₂NHCH₃,    NHSO₂(C₁-C₆alkyl), NHSO₂(C₃-C₇cycloalkyl) and N(C₁-C₆-alkyl)₂;-   each R⁸ and R⁹ are independently chosen from the group consisting of    H, C₁-C₁₀alkyl and C₃-C₇cycloalkyl; or R⁸ and R⁹ taken together form    a 4 to 6 membered aliphatic ring that optionally contains one or    more heteroatoms selected from the group consisting of N, S and O;-   R^(10b) is selected from the group consisting of H, R¹¹, OH, CN, F,    CF₂H, CF₃, CONR⁸R⁹, COOR⁸, CON(R⁸)SO₂R⁹, CON(R⁸)SO₂N(R⁸R⁹), NR⁸R⁹,    NR⁸COOR⁹, OCOR⁸, O-Benzyl, NR⁸SO₂R⁹, SO₂NR⁸R⁹, SO₂R⁸, OCONR⁸R⁹,    OCONR⁸R¹², N(R⁸)CON(R⁸R⁹), N(R⁸)COOR¹², and a 4 to 6 membered    saturated ring containing one oxygen atom;-   m is an integer from 2 to 6;-   R¹¹ is selected from the group consisting of C₁-C₆ alkyl,    C₃-C₇cycloalkyl, phenyl, pyridinyl and pyrazolyl; each optionally    substituted with one or more substituents each independently    selected from the group consisting of CF₃, CH₃, OCH₃, OCF₃ and    halogen;-   R¹² is selected from the group consisting of phenyl, pyridinyl and    pyrazolyl; each optionally substituted with one or more substituents    each independently selected from the group consisting of CF₃, CH₃,    OCH₃, OCF₃ and halogen;-    or R¹² is C₁-C₆ alkyl or C₃-C₇cycloalkyl; each substituted with one    or more substituents each independently selected from the group    consisting of CF₃, CH₃, OCH₃, OCF₃ and halogen;    -   R^(1c) is present when Het has formula (c);-   each R^(1c) is selected independently from the group consisting of    H, halogen, C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, N(R⁶)₂,    CO(R^(7c)), CH₂NH₂, CH₂OH, CN, C(═NOH)NH₂, C(═NOCH₃)NH₂, C(═NH)NH₂,    CF₃, OCF₃, B(OH)₂ and B(O—C₁-C₆alkyl)₂;-   R^(3c) is selected from the group consisting of H, halogen,    C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy and CO(R^(7c));-   R^(2c) is —(CR⁸R⁹)_(m)—R^(10c);-   R^(7c) is selected from the group consisting of OH, O(C₁-C₆alkyl),    NH₂, NHSO₂N(C₁-C₆alkyl)₂, NHSO₂NHCH₃, NHSO₂(C₁-C₆alkyl),    NHSO₂(C₃-C₇cycloalkyl), N(C₁-C₆-alkyl)₂, NR⁸R⁹ and NR⁹R^(10c);-   R^(10c) is selected from the group consisting of H, C₁-C₆alkyl, OH,    CN, F, CF₂H, CF₃, C(═NOH)NH₂, CONR⁸R⁹, COOR⁸, CONR⁸SO₂R⁹,    CON(R⁸)SO₂N(R⁸R⁹), NR⁸R⁹, NR⁸COOR⁹, OCOR⁸, NR⁸SO₂R⁹, SO₂NR⁸R⁹, SO₂R⁸    and a 4 to 6 membered saturated ring containing one oxygen atom;-   R^(1d) is present when Het has formula (d) and X is C; each R^(1d)    is selected independently from the group consisting of H, OH,    halogen, C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, N(R⁶)₂, CO(R⁷),    CH₂NH₂, CH₂OH, CN, C(═NOH)NH₂, C(═NOCH₃)NH₂, C(═NH)NH₂, CF₃, OCF₃,    B(OH)₂ and B(O—C₁-C₆alkyl)₂; R^(1d) is absent when the X to which it    is bound is N;-   R^(3d) is selected from the group consisting of H, halogen,    C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, and CO(R⁷);-   R^(2d) is —(CR⁸R⁹)_(m)—R^(10d);-   R^(10d) is selected from the group consisting of H, C₁-C₆alkyl, OH,    CN, F, CF₂H, CF₃, CONR⁸R⁹, COOR⁸, CONR⁸SO₂R⁹, CON(R⁸)SO₂N(R⁸R⁹),    NR⁸R⁹, NR⁸COOR₉, OCOR⁸, NR⁸SO₂R⁹, SO₂NR⁸R⁹, SO₂R⁸ and a 4 to 6    membered saturated ring containing one oxygen atom;-   each Y independently is C or N;-   R^(1e) is present when Het has formula (e) and Y is C; each R^(1e)    is selected independently from the group consisting of H, halogen,    C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, N(R⁶)₂, CO(R⁷), CH₂NH₂,    CH₂OH, CN, C(═NOH)NH₂, C(═NOCH₃)NH₂, C(═NH)NH₂, CF₃, OCF₃, B(OH)₂    and B(O—C₁-C₆alkyl)₂; R^(1e) is absent when the Y to which it is    bound is N;-   R^(3e) is selected from the group consisting of H, halogen,    —(CR⁸R⁹)_(m)—R^(10e), C≡C—CH₂—R^(10e), C≡C—R^(10e) and C═C—R^(10e);-   R^(10e) is selected from the group consisting of H, C₁-C₆alkyl,    C₁-C₆alkyloxy, C₃-C₇cycloalkyl, OH, CN, F, CF₂H, CF₃, CONR⁸R⁹,    COOR⁸, CON(R⁸)SO₂R⁹, CON(R⁸)SO₂N(R⁸R⁹), NR⁸R⁹, NR⁸COOR⁹, OCOR⁸,    NR⁸SO₂R⁹, SO₂NR⁸R⁹, SO₂R⁸ and a 4 to 6 membered saturated ring    containing one oxygen atom;-   R⁴ is Het¹;-   Het¹ represents a 4 to 6 membered saturated ring containing one N    atom, optionally being substituted with one or more substituents    each independently selected from the group consisting of halo,    C₁-C₄alkyloxy, SO₂R⁸, C₁-C₄alkylcarbonyl, C₁-C₄alkyloxycarbonyl,    pyridinyl, CF₃, SO₂N(C₁-C₄alkyl)₂, SO₂NH(C₁-C₄alkyl),    (C═O)NH(C₁₋₄alkyl), (C═S)NH(C₁₋₄alkyl), C₁-C₄alkyl and C₁-C₄alkyl    substituted with one hydroxy; or-    Het¹ represents a 4 to 6 membered saturated ring containing one O    atom, substituted with one or more substituents each independently    selected from the group consisting of halo, C₁-C₄alkyloxy, CF₃,    NH(C═O)(C₁₋₄alkyl), (C═O)NH(C₁₋₄alkyl) and C₁-C₄alkyl;-   Z is C or N; R⁵ is present where Z is C, whereby R⁵ is selected form    the group consisting of hydrogen, CF₃ and halogen; R⁵ is absent    where Z is N;    and the pharmaceutically acceptable addition salts, and the solvates    thereof.

In an embodiment, the present invention concerns novel compounds ofFormula (I) and stereoisomeric forms thereof, wherein Het is aheterocycle having formula (b), (c), (d) or (e);

-   each X independently is C or N; provided that at least one X is N;-   R^(1b) is present when Het has formula (b) and X is C; each R^(1b)    is selected independently from the group consisting of H, halogen,    C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, N(R⁶)₂, CO(R⁷), CH₂NH₂,    CH₂OH, CN, C(═NOH)NH₂, C(═NOCH₃)NH₂, C(═NH)NH₂, CF₃, OCF₃, B(OH)₂    and B(O—C₁-C₆alkyl)₂; R^(1b) is absent when the X to which it is    bound is N;-   R^(2b) is —(CR⁸R⁹)_(m)—R^(10b);-   each R⁶ is independently selected from the group consisting of H,    C₁-C₆alkyl, COOCH₃ and CONHSO₂CH₃;-   each R⁷ is independently selected from the group consisting of OH,    C₁-C₆alkyloxy, NH₂, NHSO₂N(C₁-C₆alkyl)₂, NHSO₂NHCH₃,    NHSO₂(C₁-C₆alkyl), NHSO₂(C₃-C₇cycloalkyl) and N(C₁-C₆-alkyl)₂;-   each R⁸ and R⁹ are independently chosen from the group consisting of    H, C₁-C₁₀alkyl and C₃-C₇cycloalkyl; or R⁸ and R⁹ taken together form    a 4 to 6 membered aliphatic ring that optionally contains one or    more heteroatoms selected from the group consisting of N, S and O;-   R^(10b) is selected from the group consisting of H, R¹¹, OH, CN, F,    CF₂H, CF₃, CONR⁸R⁹, COOR⁸, CON(R⁸)SO₂R⁹, CON(R⁸)SO₂N(R⁸R⁹), NR⁸R⁹,    NR⁸COOR⁹, OCOR⁸, O-Benzyl, NR⁸SO₂R⁹, SO₂NR⁸R⁹, SO₂R⁸, OCONR⁸R⁹,    OCONR⁸R¹², N(R⁸)CON(R⁸R⁹), N(R⁸)COOR¹², and a 4 to 6 membered    saturated ring containing one oxygen atom;-   m is an integer from 2 to 6;-   R¹¹ is selected from the group consisting of C₁-C₆ alkyl,    C₃-C₇cycloalkyl, phenyl, pyridinyl and pyrazolyl; each optionally    substituted with one or more substituents each independently    selected from the group consisting of CF₃, CH₃, OCH₃, OCF₃ and    halogen;-   R¹² is selected from the group consisting of phenyl, pyridinyl and    pyrazolyl; each optionally substituted with one or more substituents    each independently selected from the group consisting of CF₃, CH₃,    OCH₃, OCF₃ and halogen;-    or R¹² is C₁-C₆ alkyl or C₃-C₇cycloalkyl; each substituted with one    or more substituents each independently selected from the group    consisting of CF₃, CH₃, OCH₃, OCF₃ and halogen;-   R^(1c) is present when Het has formula (c);-   each R^(1c) is selected independently from the group consisting of    H, halogen, C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, N(R⁶)₂,    CO(R^(7c)), CH₂NH₂, CH₂OH, CN, C(═NOH)NH₂, C(═NOCH₃)NH₂, C(═NH)NH₂,    CF₃, OCF₃, B(OH)₂ and B(O—C₁-C₆alkyl)₂;-   R^(3c) is selected from the group consisting of H, halogen,    C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy and CO(R^(7c));-   R^(2c) is —(CR⁸R⁹)_(m)—R^(10e),-   R^(7c) is selected from the group consisting of OH, O(C₁-C₆alkyl),    NH₂, NHSO₂N(C₁-C₆alkyl)₂, NHSO₂NHCH₃, NHSO₂(C₁-C₆alkyl),    NHSO₂(C₃-C₇cycloalkyl), N(C₁-C₆-alkyl)₂, NR⁸R⁹ and NR⁹R^(10c);-   R^(10c) is selected from the group consisting of H, C₁-C₆alkyl, OH,    CN, F, CF₂H, CF₃, C(═NOH)NH₂, CONR⁸R⁹, COOR⁸, CONR⁸SO₂R⁹,    CON(R⁸)SO₂N(R⁸R⁹), NR⁸R⁹, NR⁸COOR⁹, OCOR⁸, NR⁸SO₂R⁹, SO₂NR⁸R⁹, SO₂R⁸    and a 4 to 6 membered saturated ring containing one oxygen atom;-   R^(1d) is present when Het has formula (d) and X is C; each R^(1d)    is selected independently from the group consisting of H, OH,    halogen, C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, N(R⁶)₂, CO(R⁷),    CH₂NH₂, CH₂OH, CN, C(═NOH)NH₂, C(═NOCH₃)NH₂, C(═NH)NH₂, CF₃, OCF₃,    B(OH)₂ and B(O—C₁-C₆alkyl)₂; R^(1d) is absent when the X to which it    is bound is N;-   R^(1d) is selected from the group consisting of H, halogen,    C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, and CO(R⁷);-   R^(2d) is —(CR⁸R⁹)_(m)—R^(10d);-   R^(10d) is selected from the group consisting of H, C₁-C₆alkyl, OH,    CN, F, CF₂H, CF₃, CONR⁸R⁹, COOR⁸, CONR⁸SO₂R⁹, CON(R⁸)SO₂N(R⁸R⁹),    NR⁸R⁹, NR⁸COOR₉, OCOR⁸, NR⁸SO₂R⁹, SO₂NR⁸R⁹, SO₂R⁸ and a 4 to 6    membered saturated ring containing one oxygen atom;-   each Y independently is C or N;-   R^(1e) is present when Het has formula (e) and Y is C; each R^(1e)    is selected independently from the group consisting of H, halogen,    C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, N(R⁶)₂, CO(R⁷), CH₂NH₂,    CH₂OH, CN, C(═NOH)NH₂, C(═NOCH₃)NH₂, C(═NH)NH₂, CF₃, OCF₃, B(OH)₂    and B(O—C₁-C₆alkyl)₂; R^(1e) is absent when the Y to which it is    bound is N;-   R^(3e) is selected from the group consisting of H, halogen,    —(CR⁸R⁹)_(m)—R^(10e), C≡C—CH₂—R^(10e), C≡C—R^(10e) and C═C—R^(10e);-   R^(10e) is selected from the group consisting of H, C₁-C₆alkyl,    C₁-C₆alkyloxy, C₃-C₇cycloalkyl, OH, CN, F, CF₂H, CF₃, CONR⁸R⁹,    COOR⁸, CON(R⁸)SO₂R⁹, CON(R⁸)SO₂N(R⁸R⁹), NR⁸R⁹, NR⁸COOR⁹, OCOR⁸,    NR⁸SO₂R⁹, SO₂NR⁸R⁹, SO₂R⁸ and a 4 to 6 membered saturated ring    containing one oxygen atom;-   R⁴ is selected from the group consisting of aryl and Het²; in    particular Het²;-   aryl represents phenyl or naphthalenyl; said aryl optionally being    substituted with one or more substituents each independently    selected from the group consisting of halo, C₁-C₄alkyloxy,    C₁-C₄alkyl, OH, CN, CF₂H, CF₃, CONR⁸R⁹, COOR⁸, CON(R⁸)SO₂R⁹,    CON(R⁸)SO₂N(R⁸R⁹), NR⁸R⁹, NR⁸COOR⁹, OCOR⁸, NR⁸SO₂R⁹, SO₂NR⁸R⁹,    SO₂R⁸, OCONR⁸R⁹, OCONR⁸R¹², N(R⁸)CON(R⁸R⁹), N(R⁸)COOR¹²;-   Het² represents a monocyclic 5 to 6 membered aromatic heterocycle    containing one or more heteroatoms each independently selected from    the group consisting of O, S and N; or a bicyclic 8 to 12 membered    aromatic heterocycle containing one or more heteroatoms each    independently selected from the group consisting of O, S and N; said    Het² optionally being substituted with one or more substituents each    independently selected from the group consisting of halo,    C₁-C₄alkyloxy, C₁-C₄alkyl, OH, CN, CF₂H, CF₃, CONR⁸R⁹, COOR⁸,    CON(R⁸)SO₂R⁹, CON(R⁸)SO₂N(R⁸R⁹), NR⁸R⁹, NR⁸COOR⁹, OCOR⁸, NR⁸SO₂R⁹,    SO₂NR⁸R⁹, SO₂R⁸, OCONR⁸R⁹, OCONR⁸R¹², N(R⁸)CON(R⁸R⁹), N(R⁸)COOR¹²;-   Z is C or N; R⁵ is present where Z is C, whereby R⁵ is selected form    the group consisting of hydrogen, CF₃ and halogen; R⁵ is absent    where Z is N;    and the pharmaceutically acceptable addition salts, and the solvates    thereof.

In an embodiment, the present invention concerns novel compounds ofFormula (I) and stereoisomeric forms thereof, wherein Het is aheterocycle having formula (b), (c), (d) or (e);

-   each X independently is C or N; provided that at least one X is N;-   R^(1b) is present when Het has formula (b) and X is C; each R^(1b)    is selected independently from the group consisting of H, halogen,    C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, N(R⁶)₂, CO(R⁷), CH₂NH₂,    CH₂OH, CN, C(═NOH)NH₂, C(═NOCH₃)NH₂, C(═NH)NH₂, CF₃, OCF₃, B(OH)₂    and B(O—C₁-C₆alkyl)₂; R^(1b) is absent when the X to which it is    bound is N;-   R^(2b) is —(CR⁸R⁹)_(m)—R^(10b);-   each R⁶ is independently selected from the group consisting of H,    COOCH₃ and CONHSO₂CH₃;-   each R⁷ is independently selected from the group consisting of OH,    C₁-C₆alkyloxy, NH₂, NHSO₂N(C₁-C₆alkyl)₂, NHSO₂NHCH₃,    NHSO₂(C₁-C₆alkyl), NHSO₂(C₃-C₇cycloalkyl) and N(C₁-C₆-alkyl)₂;-   each R⁸ and R⁹ are independently chosen from the group consisting of    H, and C₃-C₇cycloalkyl;-   R^(10b) is selected from the group consisting of H, R¹¹, OH, CN, F,    CF₂H, CF₃, CONR⁸R⁹, COOR⁸, CON(R⁸)SO₂R⁹, CON(R⁸)SO₂N(R⁸R⁹), NR⁸R⁹,    NR⁸COOR⁹, OCOR⁸, O-Benzyl, NR⁸SO₂R⁹, SO₂NR⁸R⁹, SO₂R⁸, OCONR⁸R⁹,    OCONR⁸R¹², N(R⁸)CON(R⁸R⁹), N(R⁸)COOR¹², and a 4 to 6 membered    saturated ring containing one oxygen atom;-   m is an integer from 2 to 6;-   R¹¹ is selected from the group consisting of C₁-C₆ alkyl,    C₃-C₇cycloalkyl, phenyl, pyridinyl and pyrazolyl; each optionally    substituted with one or more substituents each independently    selected from the group consisting of CF₃, CH₃, OCH₃, OCF₃ and    halogen;-   R¹² is selected from the group consisting of phenyl, pyridinyl and    pyrazolyl; each optionally substituted with one or more substituents    each independently selected from the group consisting of CF₃, CH₃,    OCH₃, OCF₃ and halogen;-    or R¹² is C₁-C₆ alkyl or C₃-C₇cycloalkyl; each substituted with one    or more substituents each independently selected from the group    consisting of CF₃, CH₃, OCH₃, OCF₃ and halogen;-   R^(1c) is present when Het has formula (c);-   each R^(1c) is selected independently from the group consisting of    H, halogen, C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, N(R⁶)₂,    CO(R^(7c)), CH₂NH₂, CH₂OH, CN, C(═NOH)NH₂, C(═NOCH₃)NH₂, C(═NH)NH₂,    CF₃, OCF₃, B(OH)₂ and B(O—C₁-C₆alkyl)₂;-   R^(1c) is selected from the group consisting of H, halogen,    C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy and CO(R^(7c));-   R² is —(CR⁸R⁹)_(m)—R^(10c);-   R^(7c) is selected from the group consisting of OH, O(C₁-C₆alkyl),    NH₂, NHSO₂N(C₁-C₆alkyl)₂, NHSO₂NHCH₃, NHSO₂(C₁-C₆alkyl),    NHSO₂(C₃-C₇cycloalkyl), N(C₁-C₆-alkyl)₂, NR⁸R⁹ and NR⁹R^(10c);-   R^(10c) is selected from the group consisting of H, C₁-C₆alkyl, OH,    CN, F, CF₂H, CF₃, C(═NOH)NH₂, CONR⁸R⁹, COOR⁸, CONR⁸SO₂R⁹,    CON(R⁸)SO₂N(R⁸R⁹), NR⁸R⁹, NR⁸COOR⁹, OCOR⁸, NR⁸SO₂R⁹, SO₂NR⁸R⁹, SO₂R⁸    and a 4 to 6 membered saturated ring containing one oxygen atom;-   R^(1d) is present when Het has formula (d) and X is C; each R^(1d)    is selected independently from the group consisting of H, OH,    halogen, C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, N(R⁶)₂, CO(R⁷),    CH₂NH₂, CH₂OH, CN, C(═NOH)NH₂, C(═NOCH₃)NH₂, C(═NH)NH₂, CF₃, OCF₃,    B(OH)₂ and B(O—C₁-C₆alkyl)₂; R^(1d) is absent when the X to which it    is bound is N;-   R^(3d) is selected from the group consisting of H, halogen,    C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, and CO(R⁷);-   R^(2d) is —(CR⁸R⁹)_(m)—R^(10d);-   R^(10d) is selected from the group consisting of H, C₁-C₆alkyl, OH,    CN, F, CF₂H, CF₃, CONR⁸R⁹, COOR⁸, CONR⁸SO₂R⁹, CON(R⁸)SO₂N(R⁸R⁹),    NR⁸R⁹, NR⁸COOR₉, OCOR⁸, NR⁸SO₂R⁹, SO₂NR⁸R⁹, SO₂R⁸ and a 4 to 6    membered saturated ring containing one oxygen atom;-   each Y independently is C or N;-   R^(1e) is present when Het has formula (e) and Y is C; each R^(1e)    is selected independently from the group consisting of H, halogen,    C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, N(R⁶)₂, CO(R⁷), CH₂NH₂,    CH₂OH, CN, C(═NOH)NH₂, C(═NOCH₃)NH₂, C(═NH)NH₂, CF₃, OCF₃, B(OH)₂    and B(O—C₁-C₆alkyl)₂; R^(1e) is absent when the Y to which it is    bound is N;-   R^(3e) is selected from the group consisting of H, halogen,    —(CR⁸R⁹)_(m)—R^(10e), C≡C—CH₂—R^(10e), C≡C—R^(10e) and C═C—R^(10e);-   R^(10e) is selected from the group consisting of H, C₁-C₆alkyl,    C₁-C₆alkyloxy, C₃-C₇cycloalkyl, OH, CN, F, CF₂H, CF₃, CONR⁸R⁹,    COOR⁸, CON(R⁸)SO₂R⁹, CON(R⁸)SO₂N(R⁸R⁹), NR⁸R⁹, NR⁸COOR⁹, OCOR⁸,    NR⁸SO₂R⁹, SO₂NR⁸R⁹, SO₂R⁸ and a 4 to 6 membered saturated ring    containing one oxygen atom;-   R⁴ is selected from the group consisting of tert-butyl, Het¹, aryl,    Het², CH(CH₃)(CF₃), and C₃-C₇cycloalkyl substituted with one or more    substituents selected from the group consisting of halo and    C₁-C₄alkyl;-   aryl represents phenyl or naphthalenyl; said aryl optionally being    substituted with one or more substituents each independently    selected from the group consisting of halo, C₁-C₄alkyloxy,    C₁-C₄alkyl, OH, CN, CF₂H, CF₃, CONR⁸R⁹, COOR⁸, CON(R⁸)SO₂R⁹,    CON(R⁸)SO₂N(R⁸R⁹), NR⁸R⁹, NR⁸COOR⁹, OCOR⁸, NR⁸SO₂R⁹, SO₂NR⁸R⁹,    SO₂R⁸, OCONR⁸R⁹, OCONR⁸R¹², N(R⁸)CON(R⁸R⁹), N(R⁸)COOR¹²;-   Het¹ represents a 4 to 6 membered saturated ring containing one N    atom, optionally being substituted with one or more substituents    each independently selected from the group consisting of halo,    C₁-C₄alkyloxy, SO₂R⁸, C₁-C₄alkylcarbonyl, CO(aryl), COHet²,    C₁-C₄alkyloxycarbonyl, pyridinyl, CF₃, SO₂N(C₁-C₄alkyl)₂,    SO₂NH(C₁-C₄alkyl), (C═O)NH(C₁₋₄alkyl), (C═S)NH(C₁₋₄alkyl),    C₁-C₄alkyl and C₁-C₄alkyl substituted with one hydroxy; or-    Het¹ represents a 4 to 6 membered saturated ring containing one O    atom, substituted with one or more substituents each independently    selected from the group consisting of halo, C₁-C₄alkyloxy, CF₃,    NH(C═O)(C₁₋₄alkyl), (C═O)NH(C₁₋₄alkyl) and C₁-C₄alkyl;-   Het² represents a monocyclic 5 to 6 membered aromatic heterocycle    containing one or more heteroatoms each independently selected from    the group consisting of O, S and N; or a bicyclic 8 to 12 membered    aromatic heterocycle containing one or more heteroatoms each    independently selected from the group consisting of O, S and N; said    Het² optionally being substituted with one or more substituents each    independently selected from the group consisting of halo,    C₁-C₄alkyloxy, C₁-C₄alkyl, OH, CN, CF₂H, CF₃, CONR⁸R⁹, COOR⁸,    CON(R⁸)SO₂R⁹, CON(R⁸)SO₂N(R⁸R⁹), NR⁸R⁹, NR⁸COOR⁹, OCOR⁸, NR⁸SO₂R⁹,    SO₂NR⁸R⁹, SO₂R⁸, OCONR⁸R⁹, OCONR⁸R¹², N(R⁸)CON(R⁸R⁹), N(R⁸)COOR¹²;-   Z is C or N; R⁵ is present where Z is C, whereby R⁵ is selected form    the group consisting of hydrogen, CF₃ and halogen; R⁵ is absent    where Z is N;    and the pharmaceutically acceptable addition salts, and the solvates    thereof.

In an embodiment, the present invention concerns novel compounds ofFormula (I) and stereoisomeric forms thereof, wherein Het is aheterocycle having formula (b), (c), (d) or (e);

-   each X independently is C or N; provided that at least one X is N;-   R^(1b) is present when Het has formula (b) and X is C; each R^(1b)    is selected independently from the group consisting of H, halogen,    C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, N(R⁶)₂, CO(R⁷), CH₂NH₂,    CH₂OH, CN, C(═NOH)NH₂, C(═NOCH₃)NH₂, C(═NH)NH₂, CF₃, OCF₃, B(OH)₂    and B(O—C₁-C₆alkyl)₂; R^(1b) is absent when the X to which it is    bound is N;-   R^(2b) is —(CR⁸R⁹)_(m)—R^(10b);-   each R⁶ is independently selected from the group consisting of H,    C₁-C₆alkyl, COOCH₃ and CONHSO₂CH₃;-   each R⁷ is independently selected from the group consisting of OH,    C₁-C₆alkyloxy, NH₂, NHSO₂N(C₁-C₆alkyl)₂, NHSO₂NHCH₃,    NHSO₂(C₁-C₆alkyl), NHSO₂(C₃-C₇cycloalkyl) and N(C₁-C₆-alkyl)₂;-   each R⁸ and R⁹ are independently chosen from the group consisting of    H;-   R^(10b) is selected from the group consisting of H, R¹¹, OH, CN, F,    CF₂H, CF₃, CONR⁸R⁹, COOR⁸, CON(R⁸)SO₂R⁹, CON(R⁸)SO₂N(R⁸R⁹), NR⁸R⁹,    NR⁸COOR⁹, OCOR⁸, O-Benzyl, NR⁸SO₂R⁹, SO₂NR⁸R⁹, SO₂CH₃, OCONR⁸R⁹,    OCONR⁸R¹², N(R⁸)CON(R⁸R⁹), N(R⁸)COOR¹², and a 4 to 6 membered    saturated ring containing one oxygen atom;-   m is an integer from 2 to 6;-   R¹¹ is selected from the group consisting of C₁-C₆ alkyl,    C₃-C₇cycloalkyl, phenyl, pyridinyl and pyrazolyl; each optionally    substituted with one or more substituents each independently    selected from the group consisting of CF₃, CH₃, OCH₃, OCF₃ and    halogen;-   R¹² is selected from the group consisting of phenyl, pyridinyl and    pyrazolyl; each optionally substituted with one or more substituents    each independently selected from the group consisting of CF₃, CH₃,    OCH₃, OCF₃ and halogen;-    or R¹² is C₁-C₆ alkyl or C₃-C₇cycloalkyl; each substituted with one    or more substituents each independently selected from the group    consisting of CF₃, CH₃, OCH₃, OCF₃ and halogen;-   R^(1c) is present when Het has formula (c);-   each R^(1c) is selected independently from the group consisting of    H, halogen, C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, N(R⁶)₂,    CO(R^(7c)), CH₂NH₂, CH₂OH, CN, C(═NOH)NH₂, C(═NOCH₃)NH₂, C(═NH)NH₂,    CF₃, OCF₃, B(OH)₂ and B(O—C₁-C₆alkyl)₂;-   R^(3c) is selected from the group consisting of H, halogen,    C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy and CO(R^(7c));-   R^(2c) is —(CR⁸R⁹)_(m)—R^(10c);-   R^(7c) is selected from the group consisting of OH, O(C₁-C₆alkyl),    NH₂, NHSO₂N(C₁-C₆alkyl)₂, NHSO₂NHCH₃, NHSO₂(C₁-C₆alkyl),    NHSO₂(C₃-C₇cycloalkyl), N(C₁-C₆-alkyl)₂, NR⁸R⁹ and NR⁹R^(10c);-   R^(10c) is selected from the group consisting of H, C₁-C₆alkyl, OH,    CN, F, CF₂H, CF₃, C(═NOH)NH₂, CONR⁸R⁹, COOR⁸, CONR⁸SO₂R⁹,    CON(R⁸)SO₂N(R⁸R⁹), NR⁸R⁹, NR⁸COOR⁹, OCOR⁸, NR⁸SO₂R⁹, SO₂NR⁸R⁹,    SO₂CH₃ and a 4 to 6 membered saturated ring containing one oxygen    atom;-   R^(10d) is present when Het has formula (d) and X is C; each R^(1d)    is selected independently from the group consisting of H, OH,    halogen, C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, N(R⁶)₂, CO(R⁷),    CH₂NH₂, CH₂OH, CN, C(═NOH)NH₂, C(═NOCH₃)NH₂, C(═NH)NH₂, CF₃, OCF₃,    B(OH)₂ and B(O—C₁-C₆alkyl)₂; R^(1d) is absent when the X to which it    is bound is N;-   R^(3d) is selected from the group consisting of H, halogen,    C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, and CO(R⁷);-   R^(2c) is —(CR⁸R⁹)_(m)—R^(10d);-   R^(10d) is selected from the group consisting of H, C₁-C₆alkyl, OH,    CN, F, CF₂H, CF₃, CONR⁸R⁹, COOR⁸, CONR⁸SO₂R⁹, CON(R⁸)SO₂N(R⁸R⁹),    NR⁸R⁹, NR⁸COOR₉, OCOR⁸, NR⁸SO₂R⁹, SO₂NR⁸R⁹, SO₂CH₃ and a 4 to 6    membered saturated ring containing one oxygen atom;-   each Y independently is C or N;-   R^(1e) is present when Het has formula (e) and Y is C; each R^(1e)    is selected independently from the group consisting of H, halogen,    C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, N(R⁶)₂, CO(R⁷), CH₂NH₂,    CH₂OH, CN, C(═NOH)NH₂, C(═NOCH₃)NH₂, C(═NH)NH₂, CF₃, OCF₃, B(OH)₂    and B(O—C₁-C₆alkyl)₂; R^(1e) is absent when the Y to which it is    bound is N;-   R^(3e) is selected from the group consisting of H, halogen,    —(CR⁸R⁹)_(m)—R^(10e), C≡C—CH₂—R^(10e), C≡C—R^(10e) and C═C—R^(10e);-   R^(10e) is selected from the group consisting of H, C₁-C₆alkyloxy,    C₃-C₇cycloalkyl, OH, CN, F, CF₂H, CF₃, CONR⁸R⁹, COOR⁸, CON(R⁸)SO₂R⁹,    CON(R⁸)SO₂N(R⁸R⁹), NR⁸R⁹, NR⁸COOR⁹, OCOR⁸, NR⁸SO₂R⁹, SO₂NR⁸R⁹,    SO₂CH₃ and a 4 to 6 membered saturated ring containing one oxygen    atom;-   R⁴ is selected from the group consisting of tert-butyl, Het¹, aryl,    Het², CH(CH₃)(CF₃), and C₃-C₇cycloalkyl substituted with one or more    substituents selected from the group consisting of halo and    C₁-C₄alkyl;-   aryl represents phenyl or naphthalenyl; said aryl optionally being    substituted with one or more substituents each independently    selected from the group consisting of halo, C₁-C₄alkyloxy,    C₁-C₄alkyl, OH, CN, CF₂H, CF₃, CONR⁸R⁹, COOR⁸, CON(R⁸)SO₂R⁹,    CON(R⁸)SO₂N(R⁸R⁹), NR⁸R⁹, NR⁸COOR⁹, OCOR⁸, NR⁸SO₂R⁹, SO₂NR⁸R⁹,    SO₂CH₃, OCONR⁸R⁹, OCONR⁸R¹², N(R⁸)CON(R⁸R⁹), N(R⁸)COOR¹²;-   Het¹ represents a 4 to 6 membered saturated ring containing one N    atom, optionally being substituted with one or more substituents    each independently selected from the group consisting of halo,    C₁-C₄alkyloxy, SO₂CH₃, C₁-C₄alkylcarbonyl, CO(aryl), COHet²,    C₁-C₄alkyloxycarbonyl, pyridinyl, CF₃, SO₂N(C₁-C₄alkyl)₂,    SO₂NH(C₁-C₄alkyl), (C═O)NH(C₁₋₄alkyl), (C═S)NH(C₁₋₄alkyl),    C₁-C₄alkyl and C₁-C₄alkyl substituted with one hydroxy; or-    Het¹ represents a 4 to 6 membered saturated ring containing one O    atom, substituted with one or more substituents each independently    selected from the group consisting of halo, C₁-C₄alkyloxy, CF₃,    NH(C═O)(C₁₋₄alkyl), (C═O)NH(C₁₋₄alkyl) and C₁-C₄alkyl;-   Het² represents a monocyclic 5 to 6 membered aromatic heterocycle    containing one or more heteroatoms each independently selected from    the group consisting of O, S and N; or a bicyclic 8 to 12 membered    aromatic heterocycle containing one or more heteroatoms each    independently selected from the group consisting of O, S and N; said    Het² optionally being substituted with one or more substituents each    independently selected from the group consisting of halo,    C₁-C₄alkyloxy, C₁-C₄alkyl, OH, CN, CF₂H, CF₃, CONR⁸R⁹, COOR⁸,    CON(R⁸)SO₂R⁹, CON(R⁸)SO₂N(R⁸R⁹), NR⁸R⁹, NR⁸COOR⁹, OCOR⁸, NR⁸SO₂R⁹,    SO₂NR⁸R⁹, SO₂CH₃, OCONR⁸R⁹, OCONR⁸R¹², N(R⁸)CON(R⁸R⁹), N(R⁸)COOR¹²;-   Z is C or N; R⁵ is present where Z is C, whereby R⁵ is selected form    the group consisting of hydrogen, CF₃ and halogen; R⁵ is absent    where Z is N;    and the pharmaceutically acceptable addition salts, and the solvates    thereof

In an embodiment, the present invention concerns novel compounds ofFormula (I) and stereoisomeric forms thereof, wherein Het is aheterocycle having formula (b), (c), (d) or (e); in particular (b) or(c);

-   each X independently is C or N; provided that at least one X is N;-   R^(1b) is present when Het has formula (b) and X is C; each R^(1b)    is selected independently from the group consisting of H, halogen,    C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, CF₃ and OCF₃; R^(1b) is    absent when the X to which it is bound is N;-   R^(2b) is —(CR⁸R⁹)_(m)—R^(10b);-   each R⁸ and R⁹ are independently chosen from the group consisting of    H and C₁-C₁₀alkyl;-   R^(10b) is selected from the group consisting of H, R¹¹, OH, CN, F,    CF₂H, CF₃, NR⁸R⁹, SO₂NR⁸R⁹, SO₂R⁸;-   m is an integer from 2 to 6;-   R¹¹ is selected from the group consisting of C₁-C₆ alkyl,    C₃-C₇cycloalkyl, phenyl, pyridinyl and pyrazolyl; each optionally    substituted with one or more substituents each independently    selected from the group consisting of CF₃, CH₃, OCH₃, OCF₃ and    halogen; in particular C₁-C₆ alkyl;-   R¹² is selected from the group consisting of phenyl, pyridinyl and    pyrazolyl; each optionally substituted with one or more substituents    each independently selected from the group consisting of CF₃, CH₃,    OCH₃, OCF₃ and halogen;-    or R¹² is C₁-C₆ alkyl or C₃-C₇cycloalkyl; each substituted with one    or more substituents each independently selected from the group    consisting of CF₃, CH₃, OCH₃, OCF₃ and halogen;-   R^(1c) is present when Het has formula (c);-   each R^(1c) is selected independently from the group consisting of    H, halogen, C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, CF₃ and    OCF₃;-   R^(3c) is selected from the group consisting of H, halogen,    C₁-C₆alkyl;-   R^(2c) is —(CR⁸R⁹)_(m)—R^(10c);-   R^(10c) is selected from the group consisting of H, OH, CN, F, CF₂H,    CF₃, NR⁸R⁹, SO₂NR⁸R⁹, SO₂R⁸;-   R^(1d) is present when Het has formula (d) and X is C; each R^(1d)    is selected independently from the group consisting of H, halogen,    C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, CF₃ and OCF₃; R^(1d) is    absent when the X to which it is bound is N;-   R^(3d) is selected from the group consisting of H, halogen,    C₁-C₆alkyl;-   R^(2d) is —(CR⁸R⁹)_(m)—R^(10d);-   R^(10d) is selected from the group consisting of H, OH, CN, F, CF₂H,    CF₃, NR⁸R⁹, SO₂NR⁸R⁹, SO₂R⁸;-   each Y independently is C or N;-   R^(1e) is present when Het has formula (e) and Y is C; each R^(1e)    is selected independently from the group consisting of H, halogen,    C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, CF₃ and OCF₃; R^(1e) is    absent when the Y to which it is bound is N;-   R^(3e) is selected from the group consisting of H, halogen;-   R⁴ is selected from the group consisting of tert-butyl, Het¹, aryl,    Het², CH(CH₃)(CF₃), and C₃-C₇cycloalkyl substituted with one or more    substituents selected from the group consisting of halo and    C₁-C₄alkyl;-   aryl represents phenyl or naphthalenyl; said aryl optionally being    substituted with one or more substituents each independently    selected from the group consisting of halo, C₁-C₄alkyloxy,    C₁-C₄alkyl, OH, CN, CF₂H, CF₃, CONR⁸R⁹, NR⁸R⁹, NR⁸COOR⁹, SO₂NR⁸R⁹,    SO₂R⁸, OCONR⁸R⁹, OCONR⁸R¹², N(R⁸)COOR¹²;-   Het¹ represents a 4 to 6 membered saturated ring containing one N    atom, optionally being substituted with one or more substituents    each independently selected from the group consisting of halo,    C₁-C₄alkyloxy, SO₂R⁸, C₁-C₄alkylcarbonyl, C₁-C₄alkyloxycarbonyl,    pyridinyl, CF₃, SO₂N(C₁-C₄alkyl)₂, SO₂NH(C₁-C₄alkyl),    (C═O)NH(C₁₋₄alkyl), (C═S)NH(C₁₋₄alkyl), C₁-C₄alkyl and C₁-C₄alkyl    substituted with one hydroxy; or-    Het¹ represents a 4 to 6 membered saturated ring containing one O    atom, substituted with one or more substituents each independently    selected from the group consisting of halo, C₁-C₄alkyloxy, CF₃,    NH(C═O)(C₁₋₄alkyl), (C═O)NH(C₁₋₄alkyl) and C₁-C₄alkyl;-   Het² represents a monocyclic 5 to 6 membered aromatic heterocycle    containing one or more heteroatoms each independently selected from    the group consisting of O, S and N; or a bicyclic 8 to 12 membered    aromatic heterocycle containing one or more heteroatoms each    independently selected from the group consisting of O, S and N; said    Het² optionally being substituted with one or more substituents each    independently selected from the group consisting of halo,    C₁-C₄alkyloxy, C₁-C₄alkyl, OH, CN, CF₂H, CF₃, CONR⁸R⁹, NR⁸R⁹,    NR⁸COOR⁹, SO₂NR⁸R⁹, SO₂R⁸, OCONR⁸R⁹, OCONR⁸R¹², N(R⁸)COOR¹²;-   Z is C or N; R⁵ is present where Z is C, whereby R⁵ is selected form    the group consisting of hydrogen, CF₃ and halogen; in particular R⁵    is selected form the group consisting of CF₃ and halogen; R⁵ is    absent where Z is N;    and the pharmaceutically acceptable addition salts, and the solvates    thereof.

In an embodiment, the present invention concerns novel compounds ofFormula (I) and stereoisomeric forms thereof, wherein Het is aheterocycle having formula (b), (c), (d) or (e); in particular (b) or(c);

-   each X independently is C or N; provided that at least one X is N;-   R^(1b) is present when Het has formula (b) and X is C; each R^(1b)    is selected independently from the group consisting of H, halogen,    C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, CF₃ and OCF₃; R^(1b) is    absent when the X to which it is bound is N;-   R^(2b) is —(CR⁸R⁹)_(m)—R^(10b);-   each R⁸ and R⁹ are independently chosen from the group consisting of    H and C₁-C₁₀alkyl;-   R^(10b) is selected from the group consisting of H, R¹¹, OH, CN, F,    CF₂H, CF₃, NR⁸R⁹, SO₂NR⁸R⁹, SO₂R⁸;-   m is an integer from 2 to 6;-   R¹¹ is selected from the group consisting of C₁-C₆ alkyl,    C₃-C₇cycloalkyl, phenyl, pyridinyl and pyrazolyl; each optionally    substituted with one or more substituents each independently    selected from the group consisting of CF₃, CH₃, OCH₃, OCF₃ and    halogen; in particular C₁-C₆ alkyl;-   R^(1c) is present when Het has formula (c);-   each R^(1c) is selected independently from the group consisting of    H, halogen, C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, CF₃ and    OCF₃;-   R^(3c) is selected from the group consisting of H, halogen,    C₁-C₆alkyl;-   R^(2c) is —(CR⁸R⁹)_(m)—R^(10c);-   R^(10c) is selected from the group consisting of H, C₁-C₆alkyl, OH,    CN, F, CF₂H, CF₃, NR⁸R⁹, SO₂NR⁸R⁹, SO₂R⁸;-   R^(1d) is present when Het has formula (d) and X is C; each R^(1d)    is selected independently from the group consisting of H, halogen,    C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, CF₃ and OCF₃; R^(1d) is    absent when the X to which it is bound is N;-   R^(3d) is selected from the group consisting of H, halogen,    C₁-C₆alkyl;-   R^(2d) is —(CR⁸R⁹)_(m)—R^(10d);-   R^(10d) is selected from the group consisting of H, C₁-C₆alkyl, OH,    CN, F, CF₂H, CF₃, NR⁸R⁹, SO₂NR⁸R⁹, SO₂R⁸;-   each Y independently is C or N;-   R^(3e) is present when Het has formula (e) and Y is C; each R^(1e)    is selected independently from the group consisting of H, halogen,    C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, CF₃ and OCF₃; R^(1e) is    absent when the Y to which it is bound is N;-   R^(3e) is selected from the group consisting of H, halogen;-   R⁴ is selected from the group consisting of tert-butyl, Het¹, aryl,    Het², CH(CH₃)(CF₃), and C₃-C₇cycloalkyl substituted with one or more    substituents selected from the group consisting of halo and    C₁-C₄alkyl;-   aryl represents phenyl or naphthalenyl; said aryl optionally being    substituted with one or more substituents each independently    selected from the group consisting of halo, C₁-C₄alkyloxy,    C₁-C₄alkyl;-   Het¹ represents a 4 to 6 membered saturated ring containing one N    atom, optionally being substituted with one or more substituents    each independently selected from the group consisting of halo,    C₁-C₄alkyloxy, SO₂R⁸, C₁-C₄alkylcarbonyl, C₁-C₄alkyloxycarbonyl,    pyridinyl, CF₃, C₁-C₄alkyl and C₁-C₄alkyl substituted with one    hydroxy; or-    Het¹ represents a 4 to 6 membered saturated ring containing one O    atom, substituted with one or more substituents each independently    selected from the group consisting of halo, C₁-C₄alkyloxy, CF₃ and    C₁-C₄alkyl;-   Het² represents a monocyclic 5 to 6 membered aromatic heterocycle    containing one or more heteroatoms each independently selected from    the group consisting of O, S and N; or a bicyclic 8 to 12 membered    aromatic heterocycle containing one or more heteroatoms each    independently selected from the group consisting of O, S and N; said    Het² optionally being substituted with one or more substituents each    independently selected from the group consisting of halo,    C₁-C₄alkyloxy, C₁-C₄alkyl;-   Z is C or N; R⁵ is present where Z is C, whereby R⁵ is selected form    the group consisting of hydrogen, CF₃ and halogen; in particular R⁵    is selected form the group consisting of CF₃ and halogen; R⁵ is    absent where Z is N;    and the pharmaceutically acceptable addition salts, and the solvates    thereof.

In an embodiment, the present invention concerns novel compounds ofFormula (I) and stereoisomeric forms thereof, wherein Het is aheterocycle having formula (b), (c), (d) or (e);

-   each X independently is C or N; provided that at least one X is N;-   R^(1b) is present when Het has formula (b) and X is C; each R^(1b)    is selected independently from the group consisting of H, halogen,    C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, N(R⁶)₂, CO(R⁷), CH₂NH₂,    CH₂OH, CN, C(═NOH)NH₂, C(═NOCH₃)NH₂, C(═NH)NH₂, CF₃, OCF₃, B(OH)₂    and B(O—C₁-C₆alkyl)₂; R^(1b) is absent when the X to which it is    bound is N;-   R^(2b) is —(CR⁸R⁹)_(m)—R^(10b);-   each R⁶ is independently selected from the group consisting of H,    COOCH₃ and CONHSO₂CH₃;-   each R⁷ is independently selected from the group consisting of OH,    C₁-C₆alkyloxy, NH₂, NHSO₂N(C₁-C₆alkyl)₂, NHSO₂NHCH₃,    NHSO₂(C₁-C₆alkyl), NHSO₂(C₃-C₇cycloalkyl) and N(C₁-C₆-alkyl)₂;-   each R⁸ and R⁹ are independently chosen from the group consisting of    H, and C₃-C₇cycloalkyl; or R⁸ and R⁹ taken together form a 4 to 6    membered aliphatic ring that optionally contains one or more    heteroatoms selected from the group consisting of N, S and O;-   R^(10b) is selected from the group consisting of H, R¹¹, OH, CN, F,    CF₂H, CF₃, CONR⁸R⁹, COOR⁸, CON(R⁸)SO₂R⁹, CON(R⁸)SO₂N(R⁸R⁹), NR⁸R⁹,    NR⁸COOR⁹, OCOR⁸, O-Benzyl, NR⁸SO₂R⁹, SO₂NR⁸R⁹, SO₂R⁸, OCONR⁸R⁹,    OCONR⁸R¹², N(R⁸)CON(R⁸R⁹), N(R⁸)COOR¹², and a 4 to 6 membered    saturated ring containing one oxygen atom;-   m is an integer from 2 to 6;-   R¹¹ is selected from the group consisting of C₁-C₆ alkyl,    C₃-C₇cycloalkyl, phenyl, pyridinyl and pyrazolyl; each optionally    substituted with one or more substituents each independently    selected from the group consisting of CF₃, CH₃, OCH₃, OCF₃ and    halogen;-   R¹² is selected from the group consisting of phenyl, pyridinyl and    pyrazolyl; each optionally substituted with one or more substituents    each independently selected from the group consisting of CF₃, CH₃,    OCH₃, OCF₃ and halogen;-    or R¹² is C₁-C₆ alkyl or C₃-C₇cycloalkyl; each substituted with one    or more substituents each independently selected from the group    consisting of CF₃, CH₃, OCH₃, OCF₃ and halogen;-   R^(1c) is present when Het has formula (c);-   each R^(1c) is selected independently from the group consisting of    H, halogen, C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, N(R⁶)₂,    CO(R^(7c)), CH₂NH₂, CH₂OH, CN, C(═NOH)NH₂, C(═NOCH₃)NH₂, C(═NH)NH₂,    CF₃, OCF₃, B(OH)₂ and B(O—C₁-C₆alkyl)₂;-   R^(3c) is selected from the group consisting of H, halogen,    C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy and CO(R^(7c));-   R^(2c) is —(CR⁸R⁹)_(m)—R^(10c);-   R^(7c) is selected from the group consisting of OH, O(C₁-C₆alkyl),    NH₂, NHSO₂N(C₁-C₆alkyl)₂, NHSO₂NHCH₃, NHSO₂(C₁-C₆alkyl),    NHSO₂(C₃-C₇cycloalkyl), N(C₁-C₆-alkyl)₂, NR⁸R⁹ and NR⁹R^(10c);-   R^(10c) is selected from the group consisting of H, C₁-C₆alkyl, OH,    CN, F, CF₂H, CF₃, C(═NOH)NH₂, CONR⁸R⁹, COOR⁸, CONR⁸SO₂R⁹,    CON(R⁸)SO₂N(R⁸R⁹), NR⁸R⁹, NR⁸COOR⁹, OCOR⁸, NR⁸SO₂R⁹, SO₂NR⁸R⁹, SO₂R⁸    and a 4 to 6 membered saturated ring containing one oxygen atom;-   R^(1d) is present when Het has formula (d) and X is C; each R^(1d)    is selected independently from the group consisting of H, OH,    halogen, C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, N(R⁶)₂, CO(R⁷),    CH₂NH₂, CH₂OH, CN, C(═NOH)NH₂, C(═NOCH₃)NH₂, C(═NH)NH₂, CF₃, OCF₃,    B(OH)₂ and B(O—C₁-C₆alkyl)₂; R^(1d) is absent when the X to which it    is bound is N;-   R^(3d) is selected from the group consisting of H, halogen,    C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, and CO(R⁷);-   R^(2d) is —(CR⁸R⁹)_(m)—R^(10d);-   R^(10d) is selected from the group consisting of H, C₁-C₆alkyl, OH,    CN, F, CF₂H, CF₃, CONR⁸R⁹, COOR⁸, CONR⁸SO₂R⁹, CON(R⁸)SO₂N(R⁸R⁹),    NR⁸R⁹, NR⁸COOR₉, OCOR⁸, NR⁸SO₂R⁹, SO₂NR⁸R⁹, SO₂R⁸ and a 4 to 6    membered saturated ring containing one oxygen atom;-   each Y independently is C or N;-   R^(1e) is present when Het has formula (e) and Y is C; each R^(1e)    is selected independently from the group consisting of H, halogen,    C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, N(R⁶)₂, CO(R⁷), CH₂NH₂,    CH₂OH, CN, C(═NOH)NH₂, C(═NOCH₃)NH₂, C(═NH)NH₂, CF₃, OCF₃, B(OH)₂    and B(O—C₁-C₆alkyl)₂; R^(1e) is absent when the Y to which it is    bound is N;

R^(3e) is selected from the group consisting of H, halogen,—(CR⁸R⁹)_(m)—R^(10e), C≡C—CH₂—R^(10e), C≡C—R^(10e) and C═C—R^(10e);

-   R^(10e) is selected from the group consisting of H, C₁-C₆alkyl,    C₁-C₆alkyloxy, C₃-C₇cycloalkyl, OH, CN, F, CF₂H, CF₃, CONR⁸R⁹,    COOR⁸, CON(R⁸)SO₂R⁹, CON(R⁸)SO₂N(R⁸R⁹), NR⁸R⁹, NR⁸COOR⁹, OCOR⁸,    NR⁸SO₂R⁹, SO₂NR⁸R⁹, SO₂R⁸ and a 4 to 6 membered saturated ring    containing one oxygen atom;-   R⁴ is selected from the group consisting of Het¹, aryl, Het², and    C₃-C₇cycloalkyl substituted with one or more substituents selected    from the group consisting of halo and C₁-C₄alkyl; in particular    Het¹, Het², and C₃-C₇cycloalkyl substituted with one or more    substituents selected from the group consisting of halo and    C₁-C₄alkyl;-   aryl represents phenyl or naphthalenyl; said aryl optionally being    substituted with one or more substituents each independently    selected from the group consisting of halo, C₁-C₄alkyloxy,    C₁-C₄alkyl, OH, CN, CF₂H, CF₃, CONR⁸R⁹, COOR⁸, CON(R⁸)SO₂R⁹,    CON(R⁸)SO₂N(R⁸R⁹), NR⁸R⁹, NR⁸COOR⁹, OCOR⁸, NR⁸SO₂R⁹, SO₂NR⁸R⁹,    SO₂R⁸, OCONR⁸R⁹, OCONR⁸R¹², N(R⁸)CON(R⁸R⁹), N(R⁸)COOR¹²;-   Het¹ represents a 4 to 6 membered saturated ring containing one N    atom, optionally being substituted with one or more substituents    each independently selected from the group consisting of halo,    C₁-C₄alkyloxy, SO₂R⁸, C₁-C₄alkylcarbonyl, CO(aryl), COHet²,    C₁-C₄alkyloxycarbonyl, pyridinyl, CF₃, SO₂N(C₁-C₄alkyl)₂,    SO₂NH(C₁-C₄alkyl), (C═O)NH(C₁₋₄alkyl), (C═S)NH(C₁₋₄alkyl),    C₁-C₄alkyl and C₁-C₄alkyl substituted with one hydroxy; or-    Het¹ represents a 4 to 6 membered saturated ring containing one O    atom, substituted with one or more substituents each independently    selected from the group consisting of halo, C₁-C₄alkyloxy, CF₃,    NH(C═O)(C₁₋₄alkyl), (C═O)NH(C₁₋₄alkyl) and C₁-C₄alkyl;-   Het² represents a monocyclic 5 to 6 membered aromatic heterocycle    containing one or more heteroatoms each independently selected from    the group consisting of O, S and N; or a bicyclic 8 to 12 membered    aromatic heterocycle containing one or more heteroatoms each    independently selected from the group consisting of O, S and N; said    Het² optionally being substituted with one or more substituents each    independently selected from the group consisting of halo,    C₁-C₄alkyloxy, C₁-C₄alkyl, OH, CN, CF₂H, CF₃, CONR⁸R⁹, COOR⁸,    CON(R⁸)SO₂R⁹, CON(R⁸)SO₂N(R⁸R⁹), NR⁸R⁹, NR⁸COOR⁹, OCOR⁸, NR⁸SO₂R⁹,    SO₂NR⁸R⁹, SO₂R⁸, OCONR⁸R⁹, OCONR⁸R¹², N(R⁸)CON(R⁸R⁹), N(R⁸)COOR¹²;-   Z is C or N; R⁵ is present where Z is C, whereby R⁵ is selected form    the group consisting of hydrogen, CF₃ and halogen; R⁵ is absent    where Z is N;    and the pharmaceutically acceptable addition salts, and the solvates    thereof

In an embodiment, the present invention concerns novel compounds ofFormula (I) and stereoisomeric forms thereof, wherein Het is aheterocycle having formula (b), (c), (d) or (e);

-   each X independently is C or N; provided that at least one X is N;-   R^(1b) is present when Het has formula (b) and X is C; each R^(1b)    is selected independently from the group consisting of H, halogen,    C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, N(R⁶)₂, CO(R⁷), CH₂NH₂,    CH₂OH, CN, C(═NOH)NH₂, C(═NOCH₃)NH₂, C(═NH)NH₂, CF₃, OCF₃, B(OH)₂    and B(O—C₁-C₆alkyl)₂; R^(1b) is absent when the X to which it is    bound is N;-   R^(2b) is —(CR⁸R⁹)_(m)—R^(10b);-   each R⁶ is independently selected from the group consisting of H,    C₁-C₆alkyl, COOCH₃ and CONHSO₂CH₃;-   each R⁷ is independently selected from the group consisting of OH,    C₁-C₆alkyloxy, NH₂, NHSO₂N(C₁-C₆alkyl)₂, NHSO₂NHCH₃,    NHSO₂(C₁-C₆alkyl), NHSO₂(C₃-C₇cycloalkyl) and N(C₁-C₆-alkyl)₂;-   each R⁸ and R⁹ are independently chosen from the group consisting of    H, C₁-C₁₀alkyl and C₃-C₇cycloalkyl; or R⁸ and R⁹ taken together form    a 4 to 6 membered aliphatic ring that optionally contains one or    more heteroatoms selected from the group consisting of N, S and O;-   R^(10b) is selected from the group consisting of H, R¹¹, OH, CN, F,    CF₂H, CF₃, CONR⁸R⁹, COOR⁸, CON(R⁸)SO₂R⁹, CON(R⁸)SO₂N(R⁸R⁹), NR⁸R⁹,    NR⁸COOR⁹, OCOR⁸, O-Benzyl, NR⁸SO₂R⁹, SO₂NR⁸R⁹, SO₂R⁸, OCONR⁸R⁹,    OCONR⁸R¹², N(R⁸)CON(R⁸R⁹), N(R⁸)COOR¹², and a 4 to 6 membered    saturated ring containing one oxygen atom;-   m is an integer from 2 to 6;-   R¹¹ is selected from the group consisting of C₁-C₆ alkyl,    C₃-C₇cycloalkyl, phenyl, pyridinyl and pyrazolyl; each optionally    substituted with one or more substituents each independently    selected from the group consisting of CF₃, CH₃, OCH₃, OCF₃ and    halogen;-   R¹² is selected from the group consisting of phenyl, pyridinyl and    pyrazolyl; each optionally substituted with one or more substituents    each independently selected from the group consisting of CF₃, CH₃,    OCH₃, OCF₃ and halogen;-    or R¹² is C₁-C₆ alkyl or C₃-C₇cycloalkyl; each substituted with one    or more substituents each independently selected from the group    consisting of CF₃, CH₃, OCH₃, OCF₃ and halogen;-   R^(1c) is present when Het has formula (c);-   each R^(1c) is selected independently from the group consisting of    H, halogen, C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, N(R⁶)₂,    CO(R^(7c)), CH₂NH₂, CH₂OH, CN, C(═NOH)NH₂, C(═NOCH₃)NH₂, C(═NH)NH₂,    CF₃, OCF₃, B(OH)₂ and B(O—C₁-C₆alkyl)₂;-   R^(3c) is selected from the group consisting of H, halogen,    C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy and CO(R^(7c));-   R^(2c) is —(CR⁸R⁹)_(m)—R^(10c);-   R^(7c) is selected from the group consisting of OH, O(C₁-C₆alkyl),    NH₂, NHSO₂N(C₁-C₆alkyl)₂, NHSO₂NHCH₃, NHSO₂(C₁-C₆alkyl),    NHSO₂(C₃-C₇cycloalkyl), N(C₁-C₆-alkyl)₂, NR⁸R⁹ and NR⁹R^(10c);-   R^(10c) is selected from the group consisting of H, C₁-C₆alkyl, OH,    CN, F, CF₂H, CF₃, C(═NOH)NH₂, CONR⁸R⁹, COOR⁸, CONR⁸SO₂R⁹,    CON(R⁸)SO₂N(R⁸R⁹), NR⁸R⁹, NR⁸COOR⁹, OCOR⁸, NR⁸SO₂R⁹, SO₂NR⁸R⁹, SO₂R⁸    and a 4 to 6 membered saturated ring containing one oxygen atom;-   R^(1d) is present when Het has formula (d) and X is C; each R^(1d)    is selected independently from the group consisting of H, OH,    halogen, C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, N(R⁶)₂, CO(R⁷),    CH₂NH₂, CH₂OH, CN, C(═NOH)NH₂, C(═NOCH₃)NH₂, C(═NH)NH₂, CF₃, OCF₃,    B(OH)₂ and B(O—C₁-C₆alkyl)₂; R^(1d) is absent when the X to which it    is bound is N;-   R^(3d) is selected from the group consisting of H, halogen,    C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, and CO(R⁷);-   R^(2d) is —(CR⁸R⁹)_(m)—R^(10d);-   R^(10d) is selected from the group consisting of H, C₁-C₆alkyl, OH,    CN, F, CF₂H, CF₃, CONR⁸R⁹, COOR⁸, CONR⁸SO₂R⁹, CON(R⁸)SO₂N(R⁸R⁹),    NR⁸R⁹, NR⁸COOR₉, OCOR⁸, NR⁸SO₂R⁹, SO₂NR⁸R⁹, SO₂R⁸ and a 4 to 6    membered saturated ring containing one oxygen atom;-   each Y independently is C or N;-   R^(1e) is present when Het has formula (e) and Y is C; each R^(1e)    is selected independently from the group consisting of H, halogen,    C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, N(R⁶)₂, CO(R⁷), CH₂NH₂,    CH₂OH, CN, C(═NOH)NH₂, C(═NOCH₃)NH₂, C(═NH)NH₂, CF₃, OCF₃, B(OH)₂    and B(O—C₁-C₆alkyl)₂; R^(1e) is absent when the Y to which it is    bound is N;-   R^(3e) is selected from the group consisting of H, halogen,    —(CR⁸R⁹)_(m)—R^(10e), C≡C—CH₂—R^(10e), C≡C—R^(10e) and C═C—R^(10e);-   R^(10e) is selected from the group consisting of H, C₁-C₆alkyl,    C₁-C₆alkyloxy, C₃-C₇cycloalkyl, OH, CN, F, CF₂H, CF₃, CONR⁸R⁹,    COOR⁸, CON(R⁸)SO₂R⁹, CON(R⁸)SO₂N(R⁸R⁹), NR⁸R⁹, NR⁸COOR⁹, OCOR⁸,    NR⁸SO₂R⁹, SO₂NR⁸R⁹, SO₂R⁸ and a 4 to 6 membered saturated ring    containing one oxygen atom;-   R⁴ is selected from the group consisting of tert-butyl, Het¹, aryl,    Het², CH(CH₃)(CF₃), and C₃-C₇cycloalkyl substituted with one or more    substituents selected from the group consisting of halo and    C₁-C₄alkyl;-   aryl represents phenyl or naphthalenyl; said aryl optionally being    substituted with one or more substituents each independently    selected from the group consisting of halo, C₁-C₄alkyloxy,    C₁-C₄alkyl, SO₂CH₃, CF₃, SO₂N(C₁-C₄alkyl)₂, SO₂NH(C₁-C₄alkyl), CN,    (C═O)NH(C₁-C₄alkyl), (C═O)N(C₁-C₄alkyl)₂, NH(C═O)O(C₁₋₄alkyl),    O(C═O)NH(C₁-C₄alkyl) and O(C═O)N(C₁-C₄alkyl)₂;-   Het¹ represents a 4 to 6 membered saturated ring containing one N    atom, optionally being substituted with one or more substituents    each independently selected from the group consisting of halo,    C₁-C₄alkyloxy, SO₂CH₃, C₁-C₄alkylcarbonyl, C₁-C₄alkyloxycarbonyl,    pyridinyl, CF₃, SO₂N(C₁-C₄alkyl)₂, SO₂NH(C₁-C₄alkyl),    (C═O)NH(C₁₋₄alkyl), C₁-C₄alkyl and C₁-C₄alkyl substituted with one    hydroxy; or-    Het¹ represents a 4 to 6 membered saturated ring containing one O    atom, substituted with one or more substituents each independently    selected from the group consisting of halo, C₁-C₄alkyloxy, CF₃,    NH(C═O)(C₁₋₄alkyl), (C═O)NH(C₁₋₄alkyl) and C₁-C₄alkyl;-   Het² represents a monocyclic 5 to 6 membered aromatic heterocycle    containing one or more heteroatoms each independently selected from    the group consisting of O, S and N; or a bicyclic 8 to 12 membered    aromatic heterocycle containing one or more heteroatoms each    independently selected from the group consisting of O, S and N; said    Het² optionally being substituted with one or more substituents each    independently selected from the group consisting of halo,    C₁-C₄alkyloxy, C₁-C₄alkyl, SO₂CH₃, CF₃, SO₂N(C₁-C₄alkyl)₂,    SO₂NH(C₁-C₄alkyl), CN, (C═O)NH(C₁-C₄alkyl), (C═O)N(C₁-C₄alkyl)₂,    NH(C═O)O(C₁₋₄alkyl), O(C═O)NH(C₁-C₄alkyl) and O(C═O)N(C₁-C₄alkyl)₂;-   Z is C or N; R⁵ is present where Z is C, whereby R⁵ is selected form    the group consisting of hydrogen, CF₃ and halogen; R⁵ is absent    where Z is N;    and the pharmaceutically acceptable addition salts, and the solvates    thereof.

In an embodiment, the present invention concerns novel compounds ofFormula (I) and stereoisomeric forms thereof,

-   Het is a heterocycle having formula (b), (c), (d) or (e); in    particular (b) or (c); each X independently is C or N; provided that    at least one X is N;-   R^(1b) is present when Het has formula (b) and X is C; each R^(1b)    is selected independently from the group consisting of H, halogen,    C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, CH₂NH₂, CH₂OH, CN, CF₃,    OCF₃;-   R^(1b) is absent when the X to which it is bound is N;-   R^(2b) is —(CR⁸R⁹)_(m)—R^(10b);-   each R⁸ and R⁹ are independently chosen from the group consisting of    H, C₁-C₁₀alkyl and C₃-C₇cycloalkyl;-   R^(10b) is selected from the group consisting of H, R¹¹, OH, CN, F,    CF₂H, CF₃, SO₂R⁸;-   m is an integer from 2 to 6;-   R¹¹ is selected from the group consisting of C₁-C₆ alkyl optionally    substituted with one or more substituents each independently    selected from the group consisting of CF₃, CH₃, OCH₃, OCF₃ and    halogen;-   R^(1c) is present when Het has formula (c);-   each R^(1c) is selected independently from the group consisting of    H, halogen, C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, CH₂NH₂,    CH₂OH, CN, CF₃, OCF₃;-   R^(1c) is selected from the group consisting of H;-   R^(2c) is —(CR⁸R⁹)_(m)—R^(10c);-   R^(10c) is selected from the group consisting of H, C₁-C₆alkyl, OH,    CN, F, CF₂H, CF₃, SO₂R⁸;-   R^(1d) is present when Het has formula (d) and X is C; each R^(1d)    is selected independently from the group consisting of H, OH,    halogen, C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, CH₂NH₂, CH₂OH,    CN, CF₃, OCF₃;-   R^(1d) is absent when the X to which it is bound is N;-   R^(3d) is selected from the group consisting of H;-   R^(2d) is —(CR⁸R⁹)_(m)—R^(10d);-   R^(10d) is selected from the group consisting of H, C₁-C₆alkyl, OH,    CN, F, CF₂H, CF₃, SO₂R⁸;-   each Y independently is C or N;-   R^(1e) is present when Het has formula (e) and Y is C; each R^(1e)    is selected independently from the group consisting of H, halogen,    C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, CH₂NH₂, CH₂OH, CN, CF₃,    OCF₃;-   R^(1e) is absent when the Y to which it is bound is N;-   R^(3e) is selected from the group consisting of    —(CR⁸R⁹)_(m)—R^(10e);-   R^(10e) is selected from the group consisting of H, C₁-C₆alkyloxy,    C₃-C₇cycloalkyl, OH, CN, F, CF₂H, CF₃, SO₂R⁸;-   R⁴ is selected from the group consisting of tert-butyl, Het¹, aryl,    Het², CH(CH₃)(CF₃), and C₃-C₇cycloalkyl substituted with one or more    substituents selected from the group consisting of halo and    C₁-C₄alkyl;-   aryl represents phenyl or naphthalenyl; said aryl optionally being    substituted with one or more substituents each independently    selected from the group consisting of halo, C₁-C₄alkyloxy, SO₂CH₃,    CF₃, SO₂N(C₁-C₄alkyl)₂, SO₂NH(C₁-C₄alkyl), CN, (C═O)NH(C₁-C₄alkyl),    (C═O)N(C₁-C₄alkyl)₂, NH(C═O)O(C₁₋₄alkyl), O(C═O)NH(C₁-C₄alkyl) and    O(C═O)N(C₁-C₄alkyl)₂;-   Het¹ represents a 4 to 6 membered saturated ring containing one N    atom, optionally being substituted with one or more substituents    each independently selected from the group consisting of halo,    C₁-C₄alkyloxy, SO₂CH₃, C₁-C₄alkylcarbonyl, C₁-C₄alkyloxycarbonyl,    pyridinyl, CF₃, SO₂N(C₁-C₄alkyl)₂, SO₂NH(C₁-C₄alkyl),    (C═O)NH(C₁₋₄alkyl), C₁-C₄alkyl and C₁-C₄alkyl substituted with one    hydroxy; or-    Het¹ represents a 4 to 6 membered saturated ring containing one O    atom, substituted with one or more substituents each independently    selected from the group consisting of halo, C₁-C₄alkyloxy, CF₃,    NH(C═O)(C₁₋₄alkyl), (C═O)NH(C₁₋₄alkyl) and C₁-C₄alkyl;-   Het² represents a monocyclic 5 to 6 membered aromatic heterocycle    containing one or more heteroatoms each independently selected from    the group consisting of O, S and N; or a bicyclic 8 to 12 membered    aromatic heterocycle containing one or more heteroatoms each    independently selected from the group consisting of O, S and N; said    Het² optionally being substituted with one or more substituents each    independently selected from the group consisting of halo,    C₁-C₄alkyloxy, C₁-C₄alkyl, SO₂CH₃, CF₃, SO₂N(C₁-C₄alkyl)₂,    SO₂NH(C₁-C₄alkyl), CN, (C═O)NH(C₁-C₄alkyl), (C═O)N(C₁-C₄alkyl)₂,    NH(C═O)O(C₁₋₄alkyl), O(C═O)NH(C₁-C₄alkyl) and O(C═O)N(C₁-C₄alkyl)₂;-   Z is C or N; R⁵ is present where Z is C, whereby R⁵ is selected form    the group consisting of hydrogen, CF₃ and halogen; R⁵ is absent    where Z is N;    and the pharmaceutically acceptable addition salts, and the solvates    thereof.

In an embodiment, the present invention relates to those compounds offormula (I), or any subgroup thereof as mentioned in any of the otherembodiments, wherein each R⁸ and R⁹ are independently chosen from thegroup consisting of H, and C₃-C₇cycloalkyl.

In an embodiment, the present invention relates to those compounds offormula (I), or any subgroup thereof as mentioned in any of the otherembodiments, wherein R⁴ is Het¹.

In an embodiment, the present invention relates to those compounds offormula (I), or any subgroup thereof as mentioned in any of the otherembodiments, wherein R⁴ is aryl or Het²; in particular Het².

In an embodiment, the present invention relates to those compounds offormula (I), or any subgroup thereof as mentioned in any of the otherembodiments,

-   aryl represents phenyl or naphthalenyl; said aryl optionally being    substituted with one or more substituents each independently    selected from the group consisting of halo, C₁-C₄alkyloxy,    C₁-C₄alkyl;-   Het¹ represents a 4 to 6 membered saturated ring containing one N    atom, optionally being substituted with one or more substituents    each independently selected from the group consisting of halo,    C₁-C₄alkyloxy, SO₂R⁸, C₁-C₄alkylcarbonyl, C₁-C₄alkyloxycarbonyl,    pyridinyl, CF₃, C₁-C₄alkyl and C₁-C₄alkyl substituted with one    hydroxy; or-    Het¹ represents a 4 to 6 membered saturated ring containing one O    atom, substituted with one or more substituents each independently    selected from the group consisting of halo, C₁-C₄alkyloxy, CF₃ and    C₁-C₄alkyl;-   Het² represents a monocyclic 5 to 6 membered aromatic heterocycle    containing one or more heteroatoms each independently selected from    the group consisting of O, S and N; or a bicyclic 8 to 12 membered    aromatic heterocycle containing one or more heteroatoms each    independently selected from the group consisting of O, S and N; said    Het² optionally being substituted with one or more substituents each    independently selected from the group consisting of halo,    C₁-C₄alkyloxy, C₁-C₄alkyl;-   Z is C or N; R⁵ is present where Z is C, whereby R⁵ is selected form    the group consisting of hydrogen, CF₃ and halogen; in particular R⁵    is selected form the group consisting of CF₃ and halogen; R⁵ is    absent where Z is N.

In an embodiment, the present invention relates to those compounds offormula (I), or any subgroup thereof as mentioned in any of the otherembodiments, wherein

-   aryl represents phenyl or naphthalenyl; said aryl optionally being    substituted with one or more substituents each independently    selected from the group consisting of halo, C₁-C₄alkyloxy,    C₁-C₄alkyl, SO₂CH₃, CF₃, SO₂N(C₁-C₄alkyl)₂, SO₂NH(C₁-C₄alkyl), CN,    (C═O)NH(C₁-C₄alkyl), (C═O)N(C₁-C₄alkyl)₂, NH(C═O)O(C₁₋₄alkyl),    O(C═O)NH(C₁-C₄alkyl) and O(C═O)N(C₁-C₄alkyl)₂;-   Het¹ represents a 4 to 6 membered saturated ring containing one N    atom, optionally being substituted with one or more substituents    each independently selected from the group consisting of halo,    C₁-C₄alkyloxy, SO₂CH₃, C₁-C₄alkylcarbonyl, C₁-C₄alkyloxycarbonyl,    pyridinyl, CF₃, SO₂N(C₁-C₄alkyl)₂, SO₂NH(C₁-C₄alkyl),    (C═O)NH(C₁₋₄alkyl), C₁-C₄alkyl and C₁-C₄alkyl substituted with one    hydroxy; or-    Het¹ represents a 4 to 6 membered saturated ring containing one O    atom, substituted with one or more substituents each independently    selected from the group consisting of halo, C₁-C₄alkyloxy, CF₃,    NH(C═O)(C₁₋₄alkyl), (C═O)NH(C₁₋₄alkyl) and C₁-C₄alkyl;-   Het² represents a monocyclic 5 to 6 membered aromatic heterocycle    containing one or more heteroatoms each independently selected from    the group consisting of O, S and N; or a bicyclic 8 to 12 membered    aromatic heterocycle containing one or more heteroatoms each    independently selected from the group consisting of O, S and N; said    Het² optionally being substituted with one or more substituents each    independently selected from the group consisting of halo,    C₁-C₄alkyloxy, C₁-C₄alkyl, SO₂CH₃, CF₃, SO₂N(C₁-C₄alkyl)₂,    SO₂NH(C₁-C₄alkyl), CN, (C═O)NH(C₁-C₄alkyl), (C═O)N(C₁-C₄alkyl)₂,    NH(C═O)O(C₁₋₄alkyl), O(C═O)NH(C₁-C₄alkyl) and O(C═O)N(C₁-C₄alkyl)₂.

In an embodiment, the present invention concerns novel compounds ofFormula (I) and stereoisomeric forms thereof, wherein

-   Het is a heterocycle having formula (b), (c), (d) or (e);-   each X independently is C or N; provided that at least one X is N;-   R^(1b) is present when Het has formula (b) and X is C; each R^(1b)    is selected independently from the group consisting of H, halogen,    C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, N(R⁶)₂, CO(R⁷), CH₂NH₂,    CH₂OH, CN, C(═NOH)NH₂, C(═NOCH₃)NH₂, C(═NH)NH₂, CF₃, OCF₃, B(OH)₂    and B(O—C₁-C₆alkyl)₂; R^(1b) is absent when the X to which it is    bound is N;-   R^(2b) is —(CR⁸R⁹)_(m)—R^(10b);-   each R⁶ is independently selected from the group consisting of H,    COOCH₃ and CONHSO₂CH₃;-   each R⁷ is independently selected from the group consisting of OH,    C₁-C₆alkyloxy, NH₂, NHSO₂N(C₁-C₆alkyl)₂, NHSO₂NHCH₃,    NHSO₂(C₁-C₆alkyl), NHSO₂(C₃-C₇cycloalkyl) and N(C₁-C₆-alkyl)₂;-   each R⁸ and R⁹ are independently chosen from the group consisting of    H, and C₃-C₇cycloalkyl; or R⁸ and R⁹ taken together form a 4 to 6    membered aliphatic ring that optionally contains one or more    heteroatoms selected from the group consisting of N, S and O;-   R^(10b) is selected from the group consisting of H, R¹¹, OH, CN, F,    CF₂H, CF₃, CONR⁸R⁹, COOR⁸, CON(R⁸)SO₂R⁹, CON(R⁸)SO₂N(R⁸R⁹), NR⁸R⁹,    NR⁸COOR⁹, OCOR⁸, O-Benzyl, NR⁸SO₂R⁹, SO₂NR⁸R⁹, SO₂R⁸, OCONR⁸R⁹,    OCONR⁸R¹², N(R⁸)CON(R⁸R⁹), N(R⁸)COOR¹², and a 4 to 6 membered    saturated ring containing one oxygen atom;-   m is an integer from 2 to 6;-   R¹¹ is selected from the group consisting of C₁-C₆ alkyl,    C₃-C₇cycloalkyl, phenyl, pyridinyl and pyrazolyl; each optionally    substituted with one or more substituents each independently    selected from the group consisting of CF₃, CH₃, OCH₃, OCF₃ and    halogen;-   R¹² is selected from the group consisting of phenyl, pyridinyl and    pyrazolyl; each optionally substituted with one or more substituents    each independently selected from the group consisting of CF₃, CH₃,    OCH₃, OCF₃ and halogen;-    or R¹² is C₁-C₆ alkyl or C₃-C₇cycloalkyl; each substituted with one    or more substituents each independently selected from the group    consisting of CF₃, CH₃, OCH₃, OCF₃ and halogen;-   R^(1c) is present when Het has formula (c);-   each R^(1c) is selected independently from the group consisting of    H, halogen, C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, N(R⁶)₂,    CO(R^(7c)), CH₂NH₂, CH₂OH, CN, C(═NOH)NH₂, C(═NOCH₃)NH₂, C(═NH)NH₂,    CF₃, OCF₃, B(OH)₂ and B(O—C₁-C₆alkyl)₂;-   R^(3c) is selected from the group consisting of H, halogen,    C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy and CO(R^(7c));-   R^(2c) is —(CR⁸R⁹)_(m)—R^(10c);-   R^(7c) is selected from the group consisting of OH, O(C₁-C₆alkyl),    NH₂, NHSO₂N(C₁-C₆alkyl)₂, NHSO₂NHCH₃, NHSO₂(C₁-C₆alkyl),    NHSO₂(C₃-C₇cycloalkyl), N(C₁-C₆-alkyl)₂, NR⁸R⁹ and NR⁹R^(10c);-   R^(10c) is selected from the group consisting of H, C₁-C₆alkyl, OH,    CN, F, CF₂H, CF₃, C(═NOH)NH₂, CONR⁸R⁹, COOR⁸, CONR⁸SO₂R⁹,    CON(R⁸)SO₂N(R⁸R⁹), NR⁸R⁹, NR⁸COOR⁹, OCOR⁸, NR⁸SO₂R⁹, SO₂NR⁸R⁹, SO₂R⁸    and a 4 to 6 membered saturated ring containing one oxygen atom;-   R^(1d) is present when Het has formula (d) and X is C; each R^(1d)    is selected independently from the group consisting of H, OH,    halogen, C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, N(R⁶)₂, CO(R⁷),    CH₂NH₂, CH₂OH, CN, C(═NOH)NH₂, C(═NOCH₃)NH₂, C(═NH)NH₂, CF₃, OCF₃,    B(OH)₂ and B(O—C₁-C₆alkyl)₂; R^(1d) is absent when the X to which it    is bound is N;-   R^(3d) is selected from the group consisting of H, halogen,    C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, and CO(R⁷);-   R^(2d) is —(CR⁸R⁹)_(m)—R^(10d);-   R^(10d) is selected from the group consisting of H, C₁-C₆alkyl, OH,    CN, F, CF₂H, CF₃, CONR⁸R⁹, COOR⁸, CONR⁸SO₂R⁹, CON(R⁸)SO₂N(R⁸R⁹),    NR⁸R⁹, NR⁸COOR₉, OCOR⁸, NR⁸SO₂R⁹, SO₂NR⁸R⁹, SO₂R⁸ and a 4 to 6    membered saturated ring containing one oxygen atom;-   each Y independently is C or N;-   R^(1e) is present when Het has formula (e) and Y is C; each R^(1e)    is selected independently from the group consisting of H, halogen,    C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, N(R⁶)₂, CO(R⁷), CH₂NH₂,    CH₂OH, CN, C(═NOH)NH₂, C(═NOCH₃)NH₂, C(═NH)NH₂, CF₃, OCF₃, B(OH)₂    and B(O—C₁-C₆alkyl)₂; R^(1e) is absent when the Y to which it is    bound is N;-   R^(3e) is selected from the group consisting of H, halogen,    —(CR⁸R⁹)_(m)—R^(10e), C≡C—CH₂—R^(10e), C≡C—R^(10e) and C═C—R^(10e);-   R^(10e) is selected from the group consisting of H, C₁-C₆alkyl,    C₁-C₆alkyloxy, C₃-C₇cycloalkyl, OH, CN, F, CF₂H, CF₃, CONR⁸R⁹,    COOR⁸, CON(R⁸)SO₂R⁹, CON(R⁸)SO₂N(R⁸R⁹), NR⁸R⁹, NR⁸COOR⁹, OCOR⁸,    NR⁸SO₂R⁹, SO₂NR⁸R⁹, SO₂R⁸ and a 4 to 6 membered saturated ring    containing one oxygen atom;-   R⁴ is selected from the group consisting of Het¹ and C₃-C₇cycloalkyl    substituted with one or more substituents selected from the group    consisting of halo and C₁-C₄alkyl; in particular R⁴ is Het¹;-   Het¹ represents a 4 to 6 membered saturated ring containing one N    atom, optionally being substituted with one or more substituents    each independently selected from the group consisting of halo,    C₁-C₄alkyloxy, SO₂R⁸, C₁-C₄alkylcarbonyl, CO(aryl), COHet²,    C₁-C₄alkyloxycarbonyl, pyridinyl, CF₃, SO₂N(C₁-C₄alkyl)₂,    SO₂NH(C₁-C₄alkyl), (C═O)NH(C₁₋₄alkyl), (C═S)NH(C₁₋₄alkyl),    C₁-C₄alkyl and C₁-C₄alkyl substituted with one hydroxy; or-    Het¹ represents a 4 to 6 membered saturated ring containing one O    atom, substituted with one or more substituents each independently    selected from the group consisting of halo, C₁-C₄alkyloxy, CF₃,    NH(C═O)(C₁₋₄alkyl), (C═O)NH(C₁₋₄alkyl) and C₁-C₄alkyl;-   aryl represents phenyl or naphthalenyl; said aryl optionally being    substituted with one or more substituents each independently    selected from the group consisting of halo, C₁-C₄alkyloxy,    C₁-C₄alkyl, OH, CN, CF₂H, CF₃, CONR⁸R⁹, COOR⁸, CON(R⁸)SO₂R⁹,    CON(R⁸)SO₂N(R⁸R⁹), NR⁸R⁹, NR⁸COOR⁹, OCOR⁸, NR⁸SO₂R⁹, SO₂NR⁸R⁹,    SO₂R⁸, OCONR⁸R⁹, OCONR⁸R¹², N(R⁸)CON(R⁸R⁹), N(R⁸)COOR¹²;-   Het² represents a monocyclic 5 to 6 membered aromatic heterocycle    containing one or more heteroatoms each independently selected from    the group consisting of O, S and N; or a bicyclic 8 to 12 membered    aromatic heterocycle containing one or more heteroatoms each    independently selected from the group consisting of O, S and N; said    Het² optionally being substituted with one or more substituents each    independently selected from the group consisting of halo,    C₁-C₄alkyloxy, C₁-C₄alkyl, OH, CN, CF₂H, CF₃, CONR⁸R⁹, COOR⁸,    CON(R⁸)SO₂R⁹, CON(R⁸)SO₂N(R⁸R⁹), NR⁸R⁹, NR⁸COOR⁹, OCOR⁸, NR⁸SO₂R⁹,    SO₂NR⁸R⁹, SO₂R⁸, OCONR⁸R⁹, OCONR⁸R¹², N(R⁸)CON(R⁸R⁹), N(R⁸)COOR¹²;-   Z is C or N; R⁵ is present where Z is C, whereby R⁵ is selected form    the group consisting of hydrogen, CF₃ and halogen; R⁵ is absent    where Z is N;    and the pharmaceutically acceptable addition salts, and the solvates    thereof.

In an embodiment, the present invention concerns novel compounds ofFormula (I) and stereoisomeric forms thereof, wherein

-   Het is a heterocycle having formula (b), (c), (d) or (e);-   each X independently is C or N; provided that at least one X is N;-   R^(1b) is present when Het has formula (b) and X is C; each R^(1b)    is selected independently from the group consisting of H, halogen,    C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, N(R⁶)₂, CO(R⁷), CH₂NH₂,    CH₂OH, CN, C(═NOH)NH₂, C(═NOCH₃)NH₂, C(═NH)NH₂, CF₃, OCF₃, B(OH)₂    and B(O—C₁-C₆alkyl)₂; R^(1b) is absent when the X to which it is    bound is N;-   R^(2b) is —(CR⁸R⁹)_(m)—R^(10b);-   each R⁶ is independently selected from the group consisting of H,    COOCH₃ and CONHSO₂CH₃;-   each R⁷ is independently selected from the group consisting of OH,    C₁-C₆alkyloxy, NH₂, NHSO₂N(C₁-C₆alkyl)₂, NHSO₂NHCH₃,    NHSO₂(C₁-C₆alkyl), NHSO₂(C₃-C₇cycloalkyl) and N(C₁-C₆-alkyl)₂;-   each R⁸ and R⁹ are independently chosen from the group consisting of    H, and C₃-C₇cycloalkyl; or R⁸ and R⁹ taken together form a 4 to 6    membered aliphatic ring that optionally contains one or more    heteroatoms selected from the group consisting of N, S and O;-   R^(10b) is selected from the group consisting of H, R¹¹, OH, CN, F,    CF₂H, CF₃, CONR⁸R⁹, COOR⁸, CON(R⁸)SO₂R⁹, CON(R⁸)SO₂N(R⁸R⁹), NR⁸R⁹,    NR⁸COOR⁹, OCOR⁸, O-Benzyl, NR⁸SO₂R⁹, SO₂NR⁸R⁹, SO₂R⁸, OCONR⁸R⁹,    OCONR⁸R¹², N(R⁸)CON(R⁸R⁹), N(R⁸)COOR¹², and a 4 to 6 membered    saturated ring containing one oxygen atom;-   m is an integer from 2 to 6;-   R¹¹ is selected from the group consisting of C₁-C₆ alkyl,    C₃-C₇cycloalkyl, phenyl, pyridinyl and pyrazolyl; each optionally    substituted with one or more substituents each independently    selected from the group consisting of CF₃, CH₃, OCH₃, OCF₃ and    halogen;-   R¹² is selected from the group consisting of phenyl, pyridinyl and    pyrazolyl; each optionally substituted with one or more substituents    each independently selected from the group consisting of CF₃, CH₃,    OCH₃, OCF₃ and halogen;-    or R¹² is C₁-C₆ alkyl or C₃-C₇cycloalkyl; each substituted with one    or more substituents each independently selected from the group    consisting of CF₃, CH₃, OCH₃, OCF₃ and halogen;-   R^(1c) is present when Het has formula (c);-   each R^(1c) is selected independently from the group consisting of    H, halogen, C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, N(R⁶)₂,    CO(R^(7c)), CH₂NH₂, CH₂OH, CN, C(═NOH)NH₂, C(═NOCH₃)NH₂, C(═NH)NH₂,    CF₃, OCF₃, B(OH)₂ and B(O—C₁-C₆alkyl)₂;-   R^(3c) is selected from the group consisting of H, halogen,    C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy and CO(R^(7c));-   R^(2c) is —(CR⁸R⁹)_(m)—R^(10c);-   R^(7c) is selected from the group consisting of OH, O(C₁-C₆alkyl),    NH₂, NHSO₂N(C₁-C₆alkyl)₂, NHSO₂NHCH₃, NHSO₂(C₁-C₆alkyl),    NHSO₂(C₃-C₇cycloalkyl), N(C₁-C₆-alkyl)₂, NR⁸R⁹ and NR⁹R^(10c);-   R^(10c) is selected from the group consisting of H, C₁-C₆alkyl, OH,    CN, F, CF₂H, CF₃, C(═NOH)NH₂, CONR⁸R⁹, COOR⁸, CONR⁸SO₂R⁹,    CON(R⁸)SO₂N(R⁸R⁹), NR⁸R⁹, NR⁸COOR⁹, OCOR⁸, NR⁸SO₂R⁹, SO₂NR⁸R⁹, SO₂R⁸    and a 4 to 6 membered saturated ring containing one oxygen atom;-   R^(10d) is present when Het has formula (d) and X is C; each R^(1d)    is selected independently from the group consisting of H, OH,    halogen, C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, N(R⁶)₂, CO(R⁷),    CH₂NH₂, CH₂OH, CN, C(═NOH)NH₂, C(═NOCH₃)NH₂, C(═NH)NH₂, CF₃, OCF₃,    B(OH)₂ and B(O—C₁-C₆alkyl)₂; R^(1d) is absent when the X to which it    is bound is N;-   R^(3d) is selected from the group consisting of H, halogen,    C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, and CO(R⁷);-   R^(2d) is —(CR⁸R⁹)_(m)—R^(10d);-   R^(10d) is selected from the group consisting of H, C₁-C₆alkyl, OH,    CN, F, CF₂H, CF₃, CONR⁸R⁹, COOR⁸, CONR⁸SO₂R⁹, CON(R⁸)SO₂N(R⁸R⁹),    NR⁸R⁹, NR⁸COOR₉, OCOR⁸, NR⁸SO₂R⁹, SO₂NR⁸R⁹, SO₂R⁸ and a 4 to 6    membered saturated ring containing one oxygen atom;-   each Y independently is C or N;-   R^(1e) is present when Het has formula (e) and Y is C; each R^(1e)    is selected independently from the group consisting of H, halogen,    C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, N(R⁶)₂, CO(R⁷), CH₂NH₂,    CH₂OH, CN, C(═NOH)NH₂, C(═NOCH₃)NH₂, C(═NH)NH₂, CF₃, OCF₃, B(OH)₂    and B(O—C₁-C₆alkyl)₂; R^(1e) is absent when the Y to which it is    bound is N;-   R^(3e) is selected from the group consisting of H, halogen,    —(CR⁸R⁹)_(m)—R^(10e), C≡C—CH₂—R^(10e), C≡C—R^(10e) and C═C—R^(10e);-   R^(10e) is selected from the group consisting of H, C₁-C₆alkyl,    C₁-C₆alkyloxy, C₃-C₇cycloalkyl, OH, CN, F, CF₂H, CF₃, CONR⁸R⁹,    COOR⁸, CON(R⁸)SO₂R⁹, CON(R⁸)SO₂N(R⁸R⁹), NR⁸R⁹, NR⁸COOR⁹, OCOR⁸,    NR⁸SO₂R⁹, SO₂NR⁸R⁹, SO₂R⁸ and a 4 to 6 membered saturated ring    containing one oxygen atom;-   R⁴ is selected from the group consisting of Het¹ and C₃-C₇cycloalkyl    substituted with one or more substituents selected from the group    consisting of halo and C₁-C₄alkyl; in particular R⁴ is Het¹;-   Het¹ represents a 4 to 6 membered saturated ring containing one N    atom, optionally being substituted with one or more substituents    each independently selected from the group consisting of halo,    C₁-C₄alkyloxy, SO₂R⁸, C₁-C₄alkylcarbonyl, C₁-C₄alkyloxycarbonyl,    pyridinyl, CF₃, SO₂N(C₁-C₄alkyl)₂, SO₂NH(C₁-C₄alkyl),    (C═O)NH(C₁₋₄alkyl), (C═S)NH(C₁₋₄alkyl), C₁-C₄alkyl and C₁-C₄alkyl    substituted with one hydroxy; or-    Het¹ represents a 4 to 6 membered saturated ring containing one O    atom, substituted with one or more substituents each independently    selected from the group consisting of halo, C₁-C₄alkyloxy, CF₃,    NH(C═O)(C₁₋₄alkyl), (C═O)NH(C₁₋₄alkyl) and C₁-C₄alkyl;-   Z is C or N; R⁵ is present where Z is C, whereby R⁵ is selected form    the group consisting of hydrogen, CF₃ and halogen; R⁵ is absent    where Z is N;    and the pharmaceutically acceptable addition salts, and the solvates    thereof.

In an embodiment, the present invention concerns novel compounds ofFormula (I) and stereoisomeric forms thereof, wherein

-   Het is a heterocycle having formula (b), (c), (d) or (e);-   each X independently is C or N; provided that at least one X is N;-   R^(1b) is present when Het has formula (b) and X is C; each R^(1b)    is selected independently from the group consisting of H, halogen,    C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, N(R⁶)₂, CO(R⁷), CH₂NH₂,    CH₂OH, CN, C(═NOH)NH₂, C(═NOCH₃)NH₂, C(═NH)NH₂, CF₃, OCF₃, B(OH)₂    and B(O—C₁-C₆alkyl)₂; R^(1b) is absent when the X to which it is    bound is N;-   R^(2b) is —(CR⁸R⁹)_(m)—R^(10b);-   each R⁶ is independently selected from the group consisting of H,    C₁-C₆alkyl, COOCH₃ and CONHSO₂CH₃;-   each R⁷ is independently selected from the group consisting of OH,    C₁-C₆alkyloxy, NH₂, NHSO₂N(C₁-C₆alkyl)₂, NHSO₂NHCH₃,    NHSO₂(C₁-C₆alkyl), NHSO₂(C₃-C₇cycloalkyl) and N(C₁-C₆-alkyl)₂;-   each R⁸ and R⁹ are independently chosen from the group consisting of    H, C₁-C₁₀alkyl and C₃-C₇cycloalkyl; or R⁸ and R⁹ taken together form    a 4 to 6 membered aliphatic ring that optionally contains one or    more heteroatoms selected from the group consisting of N, S and O;-   R^(10b) is selected from the group consisting of H, R¹¹, OH, CN, F,    CF₂H, CF₃, CONR⁸R⁹, COOR⁸, CON(R⁸)SO₂R⁹, CON(R⁸)SO₂N(R⁸R⁹), NR⁸R⁹,    NR⁸COOR⁹, OCOR⁸, O-Benzyl, NR⁸SO₂R⁹, SO₂NR⁸R⁹, SO₂R⁸, OCONR⁸R⁹,    OCONR⁸R¹², N(R⁸)CON(R⁸R⁹), N(R⁸)COOR¹², and a 4 to 6 membered    saturated ring containing one oxygen atom;-   m is an integer from 2 to 6;-   R¹¹ is selected from the group consisting of C₁-C₆ alkyl,    C₃-C₇cycloalkyl, phenyl, pyridinyl and pyrazolyl; each optionally    substituted with one or more substituents each independently    selected from the group consisting of CF₃, CH₃, OCH₃, OCF₃ and    halogen;-   R¹² is selected from the group consisting of phenyl, pyridinyl and    pyrazolyl; each optionally substituted with one or more substituents    each independently selected from the group consisting of CF₃, CH₃,    OCH₃, OCF₃ and halogen;-    or R¹² is C₁-C₆ alkyl or C₃-C₇cycloalkyl; each substituted with one    or more substituents each independently selected from the group    consisting of CF₃, CH₃, OCH₃, OCF₃ and halogen;-   R^(1c) is present when Het has formula (c);-   each R^(1c) is selected independently from the group consisting of    H, halogen, C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, N(R⁶)₂,    CO(R^(7c)), CH₂NH₂, CH₂OH, CN, C(═NOH)NH₂, C(═NOCH₃)NH₂, C(═NH)NH₂,    CF₃, OCF₃, B(OH)₂ and B(O—C₁-C₆alkyl)₂;-   R^(3c) is selected from the group consisting of H, halogen,    C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy and CO(R^(7c));-   R^(2c) is —(CR⁸R⁹)_(m)—R^(10c);-   R^(7c) is selected from the group consisting of OH, O(C₁-C₆alkyl),    NH₂, NHSO₂N(C₁-C₆alkyl)₂, NHSO₂NHCH₃, NHSO₂(C₁-C₆alkyl),    NHSO₂(C₃-C₇cycloalkyl), N(C₁-C₆-alkyl)₂, NR⁸R⁹ and NR⁹R^(10c);-   R^(10c) is selected from the group consisting of H, C₁-C₆alkyl, OH,    CN, F, CF₂H, CF₃, C(═NOH)NH₂, CONR⁸R⁹, COOR⁸, CONR⁸SO₂R⁹,    CON(R⁸)SO₂N(R⁸R⁹), NR⁸R⁹, NR⁸COOR⁹, OCOR⁸, NR⁸SO₂R⁹, SO₂NR⁸R⁹, SO₂R⁸    and a 4 to 6 membered saturated ring containing one oxygen atom;-   R^(1d) is present when Het has formula (d) and X is C; each R^(1d)    is selected independently from the group consisting of H, OH,    halogen, C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, N(R⁶)₂, CO(R⁷),    CH₂NH₂, CH₂OH, CN, C(═NOH)NH₂, C(═NOCH₃)NH₂, C(═NH)NH₂, CF₃, OCF₃,    B(OH)₂ and B(O—C₁-C₆alkyl)₂; R^(1d) is absent when the X to which it    is bound is N;-   R^(3d) is selected from the group consisting of H, halogen,    C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, and CO(R⁷);-   R^(2d) is —(CR⁸R⁹)_(m)—R^(10d);-   R^(10d) is selected from the group consisting of H, C₁-C₆alkyl, OH,    CN, F, CF₂H, CF₃, CONR⁸R⁹, COOR⁸, CONR⁸SO₂R⁹, CON(R⁸)SO₂N(R⁸R⁹),    NR⁸R⁹, NR⁸COOR₉, OCOR⁸, NR⁸SO₂R⁹, SO₂NR⁸R⁹, SO₂R⁸ and a 4 to 6    membered saturated ring containing one oxygen atom;-   each Y independently is C or N;-   R^(1e) is present when Het has formula (e) and Y is C; each R^(1e)    is selected independently from the group consisting of H, halogen,    C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, N(R⁶)₂, CO(R⁷), CH₂NH₂,    CH₂OH, CN, C(═NOH)NH₂, C(═NOCH₃)NH₂, C(═NH)NH₂, CF₃, OCF₃, B(OH)₂    and B(O—C₁-C₆alkyl)₂; R^(1e) is absent when the Y to which it is    bound is N;-   R^(3e) is selected from the group consisting of H, halogen,    —(CR⁸R⁹)_(m)—R^(10e), C≡C—CH₂—R^(10e) C≡C—R^(10e) and C═C—R^(10e);-   R^(10e) is selected from the group consisting of H, C₁-C₆alkyl,    C₁-C₆alkyloxy, C₃-C₇cycloalkyl, OH, CN, F, CF₂H, CF₃, CONR⁸R⁹,    COOR⁸, CON(R⁸)SO₂R⁹, CON(R⁸)SO₂N(R⁸R⁹), NR⁸R⁹, NR⁸COOR⁹, OCOR⁸,    NR⁸SO₂R⁹, SO₂NR⁸R⁹, SO₂R⁸ and a 4 to 6 membered saturated ring    containing one oxygen atom;-   R⁴ is selected from the group consisting of Het¹ and C₃-C₇cycloalkyl    substituted with one or more substituents selected from the group    consisting of halo and C₁-C₄alkyl; in particular R⁴ is Het1;-   Het¹ represents a 4 to 6 membered saturated ring containing one N    atom, optionally being substituted on the nitrogen atom with one    substituent selected from the group consisting of halo,    C₁-C₄alkyloxy, SO₂R⁸, C₁-C₄alkylcarbonyl, C₁-C₄alkyloxycarbonyl,    pyridinyl, CF₃, SO₂N(C₁-C₄alkyl)₂, SO₂NH(C₁-C₄alkyl),    (C═O)NH(C₁₋₄alkyl), (C═S)NH(C₁₋₄alkyl), C₁-C₄alkyl and C₁-C₄alkyl    substituted with one hydroxy; or-    Het¹ represents a 4 to 6 membered saturated ring containing one O    atom, wherein the carbon atom attached to the remainder of the    molecule is substituted with one substituent selected from the group    consisting of halo, C₁-C₄alkyloxy, CF₃, NH(C═O)(C₁₋₄alkyl),    (C═O)NH(C₁₋₄alkyl) and C₁-C₄alkyl; in particular C₁-C₄alkyl; more in    particular methyl;-   Z is C or N; R⁵ is present where Z is C, whereby R⁵ is selected form    the group consisting of hydrogen, CF₃ and halogen; R⁵ is absent    where Z is N;    and the pharmaceutically acceptable addition salts, and the solvates    thereof.

In an embodiment, the present invention relates to those compounds offormula (I), or any subgroup thereof as mentioned in any of the otherembodiments, wherein

-   Het¹ represents a 4 to 6 membered saturated ring containing one N    atom, optionally being substituted on the nitrogen atom with one    substituent selected from the group consisting of halo,    C₁-C₄alkyloxy, SO₂R⁸, C₁-C₄alkylcarbonyl, CO(aryl), COHet²,    C₁-C₄alkyloxycarbonyl, pyridinyl, CF₃, SO₂N(C₁-C₄alkyl)₂,    SO₂NH(C₁-C₄alkyl), (C═O)NH(C₁₋₄alkyl), (C═S)NH(C₁₋₄alkyl),    C₁-C₄alkyl and C₁-C₄alkyl substituted with one hydroxy; or-    Het¹ represents a 4 to 6 membered saturated ring containing one O    atom, wherein the carbon atom attached to the remainder of the    molecule is substituted with one substituent selected from the group    consisting of halo, C₁-C₄alkyloxy, CF₃, NH(C═O)(C₁₋₄alkyl),    (C═O)NH(C₁₋₄alkyl) and C₁-C₄alkyl; in particular C₁-C₄alkyl; more in    particular

In an embodiment, the present invention relates to those compounds offormula (I), or any subgroup thereof as mentioned in any of the otherembodiments, wherein R⁴ is selected from the group consisting of Het¹and C₃-C₇cycloalkyl substituted with one or more substituents selectedfrom the group consisting of halo and C₁-C₄alkyl; in particular R⁴ isHet1.

In an embodiment, the present invention relates to those compounds offormula (I), or any subgroup thereof as mentioned in any of the otherembodiments, wherein

-   R^(10b) is selected from the group consisting of H, R¹¹, OH, CN, F,    CF₂H, CF₃, CONR⁸R⁹, COOR⁸, CON(R⁸)SO₂R⁹, CON(R⁸)SO₂N(R⁸R⁹), NR⁸R⁹,    NR⁸COOR⁹, OCOR⁸, O-Benzyl, NR⁸SO₂R⁹, SO₂NR⁸R⁹, SO₂CH₃, OCONR⁸R⁹,    OCONR⁸R¹², N(R⁸)CON(R⁸R⁹), N(R⁸)COOR¹², and a 4 to 6 membered    saturated ring containing one oxygen atom;-   R^(10c) is selected from the group consisting of H, R¹¹, OH, CN, F,    CF₂H, CF₃, C(═NOH)NH₂, CONR⁸R⁹, COOR⁸, CONR⁸SO₂R⁹,    CON(R⁸)SO₂N(R⁸R⁹), NR⁸R⁹, NR⁸COOR⁹, OCOR⁸, NR⁸SO₂R⁹, SO₂NR⁸R⁹,    SO₂CH₃ and a 4 to 6 membered saturated ring containing one oxygen    atom;-   R^(10d) is selected from the group consisting of H, R¹¹, OH, CN, F,    CF₂H, CF₃, CONR⁸R⁹, COOR⁸, CONR⁸SO₂R⁹, CON(R⁸)SO₂N(R⁸R⁹), NR⁸R⁹,    NR⁸COOR₉, OCOR⁸, NR⁸SO₂R⁹, SO₂NR⁸R⁹, SO₂CH₃ and a 4 to 6 membered    saturated ring containing one oxygen atom;-   R^(10e) is selected from the group consisting of H, R¹¹,    C₁-C₆alkyloxy, OH, CN, F, CF₂H, CF₃, CONR⁸R⁹, COOR⁸, CON(R⁸)SO₂R⁹,    CON(R⁸)SO₂N(R⁸R⁹), NR⁸R⁹, NR⁸COOR⁹, OCOR⁸, NR⁸SO₂R⁹, SO₂NR⁸R⁹,    SO₂CH₃ and a 4 to 6 membered saturated ring containing one oxygen    atom.

In an embodiment, the present invention relates to those compounds offormula (I), or any subgroup thereof as mentioned in any of the otherembodiments, wherein SO₂R⁸ is restricted to SO₂CH³ orSO₂C₃-C₇cycloalkyl; in particular SO₂CH³.

In an embodiment, the present invention relates to those compounds offormula (I), or any subgroup thereof as mentioned in any of the otherembodiments, wherein R⁴ is selected from the group consisting of Het¹,aryl, Het², and C₃-C₇cycloalkyl substituted with one or moresubstituents selected from the group consisting of halo and C₁-C₄alkyl;in particular Het¹, Het², and C₃-C₇cycloalkyl substituted with one ormore substituents selected from the group consisting of halo andC₁-C₄alkyl.

In an embodiment, the present invention relates to those compounds offormula (I), or any subgroup thereof as mentioned in any of the otherembodiments, wherein R⁴ is selected from the group consisting of Het¹and C₃-C₇cycloalkyl substituted with one or more substituents selectedfrom the group consisting of halo and C₁-C₄alkyl; in particular R⁴ isHet1; and wherein

-   Het¹ represents a 4 to 6 membered saturated ring containing one N    atom, optionally being substituted on the nitrogen atom with one    substituent selected from the group consisting of halo,    C₁-C₄alkyloxy, SO₂R⁸, C₁-C₄alkylcarbonyl, CO(aryl), COHet²,    C₁-C₄alkyloxycarbonyl, pyridinyl, CF₃, SO₂N(C₁-C₄alkyl)₂,    SO₂NH(C₁-C₄alkyl), (C═O)NH(C₁₋₄alkyl), (C═S)NH(C₁₋₄alkyl),    C₁-C₄alkyl and C₁-C₄alkyl substituted with one hydroxy; or-    Het¹ represents a 4 to 6 membered saturated ring containing one O    atom, wherein the carbon atom attached to the remainder of the    molecule is substituted with one substituent selected from the group    consisting of halo, C₁-C₄alkyloxy, CF₃, NH(C═O)(C₁₋₄alkyl),    (C═O)NH(C₁₋₄alkyl) and C₁-C₄alkyl; in particular C₁-C₄alkyl; more in    particular methyl.

In an embodiment, the present invention relates to those compounds offormula (I), or any subgroup thereof as mentioned in any of the otherembodiments, wherein R⁴ is Het¹, and wherein

-   Het¹ represents a 4 to 6 membered saturated ring containing one N    atom, optionally being substituted on the nitrogen atom with one    substituent selected from the group consisting of halo,    C₁-C₄alkyloxy, SO₂R⁸, C₁-C₄alkylcarbonyl, CO(aryl), COHet²,    C₁-C₄alkyloxycarbonyl, pyridinyl, CF₃, SO₂N(C₁-C₄alkyl)₂,    SO₂NH(C₁-C₄alkyl), (C═O)NH(C₁₋₄alkyl), (C═S)NH(C₁-C₄alkyl),    C₁-C₄alkyl and C₁-C₄alkyl substituted with one hydroxy; or-    Het¹ represents a 4 to 6 membered saturated ring containing one O    atom, wherein the carbon atom attached to the remainder of the    molecule is substituted with one substituent selected from the group    consisting of halo, C₁-C₄alkyloxy, CF₃, NH(C═O)(C₁₋₄alkyl),    (C═O)NH(C₁₋₄alkyl) and C₁-C₄alkyl; in particular C₁-C₄alkyl; more in    particular methyl.

In an embodiment, the present invention relates to those compounds offormula (I), or any subgroup thereof as mentioned in any of the otherembodiments, wherein R⁴ is Het¹, and wherein

-   Het¹ represents a 4 to 6 membered saturated ring containing one O    atom, wherein the carbon atom attached to the remainder of the    molecule is substituted with one substituent selected from the group    consisting of halo, C₁-C₄alkyloxy, CF₃, NH(C═O)(C₁₋₄alkyl),    (C═O)NH(C₁₋₄alkyl) and C₁-C₄alkyl; in particular C₁-C₄alkyl; more in    particular methyl.

In an embodiment, the present invention relates to those compounds offormula (I), or any subgroup thereof as mentioned in any of the otherembodiments, wherein R⁴ is Het¹, and wherein

-   Het¹ represents a 4 membered saturated ring containing one O atom,    wherein the carbon atom attached to the remainder of the molecule is    substituted with one methyl group.

In an embodiment, the present invention concerns novel compounds ofFormula (I) and stereoisomeric forms thereof, wherein

-   Het is a heterocycle having formula (b) or (c),-   each X independently is C or N; provided that at least one X is N;-   R^(1b) is present when Het has formula (b) and X is C; each R^(1b)    is selected independently from the group consisting of H and    halogen; R^(1b) is absent when the X to which it is bound is N;-   R^(2b) is —(CR⁸R⁹)_(m)—R^(10b);-   each R⁸ and R⁹ are independently chosen from the group consisting of    H and C₁-C₁₀alkyl; in particular H and C₁-C₆ alkyl;-   R^(10b) is selected from the group consisting of F, C₁-C₆ alkyl,    CF₃, SO₂R⁸;-   m is an integer from 2 to 4;-   R^(1c) is present when Het has formula (c);-   each R^(1c) is selected independently from the group consisting of H    and halogen;-   R^(1c) is H;-   R^(2c) is —(CR⁸R⁹)_(m)—R^(10c);-   R^(10c) is selected from the group consisting of F and SO₂R⁸;-   R⁴ is selected from the group consisting of tert-butyl, Het¹, Het²,    and C₃-C₇cycloalkyl substituted with one or more substituents    selected from the group consisting of halo and C₁-C₄alkyl;-   Het¹ represents a 4 membered saturated ring containing one N atom,    optionally being substituted with one or more substituents each    independently selected from the group consisting of SO₂R⁸,    C₁-C₄alkylcarbonyl, C₁-C₄alkyloxycarbonyl and C₁-C₄alkyl substituted    with one hydroxy; or-    Het¹ represents a 4 membered saturated ring containing one O atom,    substituted with one or more substituents each independently    selected from the group consisting of C₁-C₄alkyl;-   Het² represents a monocyclic 5 membered aromatic heterocycle    containing one or more heteroatoms each independently selected from    the group consisting of S and N; or a bicyclic 10-membered aromatic    heterocycle containing one N-atom;-   Z is C or N; R⁵ is present where Z is C, whereby R⁵ is halogen; R⁵    is absent where Z is N;    and the pharmaceutically acceptable addition salts, and the solvates    thereof.

In an embodiment, the present invention concerns novel compounds ofFormula (I) and stereoisomeric forms thereof, wherein

-   Het is a heterocycle having formula (b) or (c),-   each X independently is C or N; provided that at least one X is N;-   R^(1b) is present when Het has formula (b) and X is C; each R^(1b)    is selected independently from the group consisting of H and    halogen; R^(1b) is absent when the X to which it is bound is N;-   R^(2b) is —(CR⁸R⁹)_(m)—R^(10b);-   each R⁸ and R⁹ are independently chosen from the group consisting of    H and C₁-C₁₀alkyl; in particular H and C₁-C₆ alkyl;-   R^(10b) is selected from the group consisting of F, C₁-C₆ alkyl,    CF₃, SO₂R₈;-   m is an integer from 2 to 4;-   R^(1c) is present when Het has formula (c);-   each R^(1c) is selected independently from the group consisting of H    and halogen;-   R^(3c) is H;-   R^(2c) is —(CR⁸R⁹)_(m)—R^(10c);-   R^(10c) is selected from the group consisting of F and SO₂R⁸;-   R⁴ is selected from the group consisting of tert-butyl, Het¹, Het²,    and C₃-C₇cycloalkyl substituted with one or more substituents    selected from the group consisting of halo and C₁-C₄alkyl;-   Het¹ represents a 4 membered saturated ring containing one N atom,    optionally being substituted with one or more substituents each    independently selected from the group consisting of SO₂R⁸,    C₁-C₄alkylcarbonyl, C₁-C₄alkyloxycarbonyl and C₁-C₄alkyl substituted    with one hydroxy;-   Het² represents a monocyclic 5 membered aromatic heterocycle    containing one or more heteroatoms each independently selected from    the group consisting of S and N; or a bicyclic 10-membered aromatic    heterocycle containing one N-atom;-   Z is C or N; R⁵ is present where Z is C, whereby R⁵ is halogen; R⁵    is absent where Z is N;    and the pharmaceutically acceptable addition salts, and the solvates    thereof

In an embodiment, the present invention concerns novel compounds ofFormula (I) and stereoisomeric forms thereof, wherein

-   Het is a heterocycle having formula (b) or (c),-   each X independently is C or N; provided that at least one X is N;-   R^(1b) is present when Het has formula (b) and X is C; each R^(1b)    is selected independently from the group consisting of H and    halogen; R^(1b) is absent when the X to which it is bound is N;-   R^(2b) is —(CR⁸R⁹)_(m)—R^(10b);-   each R⁸ and R⁹ are H;-   R^(10b) is selected from the group consisting of F, C₁-C₆ alkyl,    CF₃, SO₂CH₃;-   m is an integer from 2 to 4;-   R^(1c) is present when Het has formula (c);-   each R^(1c) is selected independently from the group consisting of H    and halogen;-   R^(3c) is H;-   R^(2c) is —(CR⁸R⁹)_(m)—R^(10c);-   R^(10c) is selected from the group consisting of F and SO₂CH₃;-   R⁴ is selected from the group consisting of tert-butyl, Het¹, Het²,    and C₃-C₇cycloalkyl substituted with one or more substituents    selected from the group consisting of halo and C₁-C₄alkyl;-   Het¹ represents a 4 membered saturated ring containing one N atom,    optionally being substituted with one or more substituents each    independently selected from the group consisting of SO₂CH₃,    C₁-C₄alkylcarbonyl, C₁-C₄alkyloxycarbonyl and C₁-C₄alkyl substituted    with one hydroxy;-   Het² represents a monocyclic 5 membered aromatic heterocycle    containing one or more heteroatoms each independently selected from    the group consisting of S and N; or a bicyclic 10-membered aromatic    heterocycle containing one N-atom;-   Z is C or N; R⁵ is present where Z is C, whereby R⁵ is halogen; R⁵    is absent where Z is N;    and the pharmaceutically acceptable addition salts, and the solvates    thereof

In an embodiment, the present invention concerns novel compounds ofFormula (I) and stereoisomeric forms thereof, wherein

-   Het is a heterocycle having formula (b-1a) or (c-1a),

-   R^(2b) is —(CR⁸R⁹)_(m)—R^(10b);-   each R⁸ and R⁹ are H;-   R^(10b) is selected from the group consisting of F, isopropyl, CF₃,    SO₂CH₃;-   m is an integer from 2 to 4;-   R^(3c) is H;-   R^(2c) is —(CR⁸R⁹)_(m)—R^(10c);-   R^(10c) is selected from the group consisting of F and SO₂CH₃;-   R⁴ is selected from the group consisting of tert-butyl, Het¹, Het²,    and C₃-C₇cycloalkyl substituted with one or more substituents    selected from the group consisting of halo and C₁-C₄alkyl;-   Het¹ represents a 4 membered saturated ring containing one N atom,    optionally being substituted on the nitrogen atom with one    substituent selected from the group consisting of SO₂CH₃,    methylcarbonyl, tert-butyloxycarbonyl and C₁-C₄alkyl substituted    with one hydroxy;-   Het² represents a monocyclic 5 membered aromatic heterocycle    containing one or more heteroatoms each independently selected from    the group consisting of S and N; or a bicyclic 10-membered aromatic    heterocycle containing one N-atom;-   Z is C or N; R⁵ is present where Z is C, whereby R⁵ is fluoro; R⁵ is    absent where Z is N;    and the pharmaceutically acceptable addition salts, and the solvates    thereof.

In an embodiment, the present invention relates to those compounds offormula (I), or any subgroup thereof as mentioned in any of the otherembodiments, wherein R⁵ is selected from the group consisting of CF₃ andhalogen.

In an embodiment, the present invention relates to those compounds offormula (I), or any subgroup thereof as mentioned in any of the otherembodiments, wherein R^(3e) is —(CR⁸R⁹)_(m)—R^(10e).

In an embodiment, the present invention relates to those compounds offormula (I), or any subgroup thereof as mentioned in any of the otherembodiments, wherein Het has formula (b) or (c).

In an embodiment, the present invention relates to those compounds offormula (I), or any subgroup thereof as mentioned in any of the otherembodiments, wherein Het has formula (b).

In an embodiment, the present invention relates to those compounds offormula (I), or any subgroup thereof as mentioned in any of the otherembodiments, wherein Het has formula (c).

In an embodiment, the present invention relates to those compounds offormula (I), or any subgroup thereof as mentioned in any of the otherembodiments, wherein Het has formula (d).

In an embodiment, the present invention relates to those compounds offormula (I), or any subgroup thereof as mentioned in any of the otherembodiments, wherein Het has formula (e).

In an embodiment, the present invention relates to those compounds offormula (I), or any subgroup thereof as mentioned in any of the otherembodiments, wherein Het is a heterocycle having formula (bb), (cc),(dd) or (ee); in particular (bb) or (cc); more in particular (bb); morein particular (cc); more in particular (dd); more in particular (cc);

wherein R^(1bb), R^(1cc), R1^(dd) or R^(1ee) are chloro or bromo; inparticular chloro;wherein R^(1b), R^(1c), R^(1d), R^(1e) and the other substituents aredefined according to any of the other embodiments;in a particular embodiment R^(1bb), R^(1cc), R1^(dd) or R^(1ee) arechloro; R^(1b), R^(1c), R^(1d), R^(1e) if present are H; and the othersubstituents are defined according to any of the other embodiments.

In an embodiment, the present invention relates to those compounds offormula (I), or any subgroup thereof as mentioned in any of the otherembodiments, wherein Het is a heterocycle having formula (b-1) or (c-1);in particular (b-1); also in particular (c-1);

wherein R^(1b) and R^(1c) are chloro or bromo.

In an embodiment, the present invention relates to those compounds offormula (I), or any subgroup thereof as mentioned in any of the otherembodiments, wherein Het is a heterocycle having formula (b-1a) or(c-1a); in particular (b-1a); also in particular (c-1a);

In an embodiment, the present invention relates to those compounds offormula (I), or any subgroup thereof as mentioned in any of the otherembodiments, wherein

-   R⁴ is selected from the group consisting of tert-butyl, azetidinyl    substituted on the N atom with one substituent selected from the    group consisting of C₁-C₄alkylcarbonyl and C₁-C₄alkyloxycarbonyl,-   phenyl substituted with one substituent selected from the group    consisting of F and C₁-C₄alkyloxy, and-   cyclopropyl substituted with one substituent selected from the group    consisting of C₁-C₄alkyl and F;-   Z is C or N; R⁵ is present where Z is C, whereby R⁵ is halogen; R⁵    is absent where Z is N.

In an embodiment, the present invention relates to those compounds offormula (I), or any subgroup thereof as mentioned in any of the otherembodiments, wherein

-   R⁴ is selected from the group consisting of tert-butyl, Het¹, Het²,    and C₃-C₇cycloalkyl substituted with one or more substituents    selected from the group consisting of halo and C₁-C₄alkyl;-   Het¹ represents a 4 membered saturated ring containing one N atom,    optionally being substituted on the nitrogen atom with one    substituent selected from the group consisting of SO₂CH₃,    C₁-C₄alkylcarbonyl, C₁-C₄alkyloxycarbonyl and C₁-C₄alkyl substituted    with one hydroxy;-   Het² represents a monocyclic 5 membered aromatic heterocycle    containing one or more heteroatoms each independently selected from    the group consisting of S and N; or a bicyclic 10-membered aromatic    heterocycle containing one N-atom;-   Z is C or N; R⁵ is present where Z is C, whereby R⁵ is halo; R⁵ is    absent where Z is N.

In an embodiment, the present invention relates to those compounds offormula (I), or any subgroup thereof as mentioned in any of the otherembodiments, wherein R⁴ is selected from the group consisting oftert-butyl, Het¹, aryl, Het² and C₃-C₇cycloalkyl substituted with one ormore substituents selected from the group consisting of halo andC₁-C₄alkyl.

In an embodiment, the present invention relates to those compounds offormula (I), or any subgroup thereof as mentioned in any of the otherembodiments, wherein R⁴ is selected from the group consisting oftert-butyl, Het¹, CH(CH₃)(CF₃), and C₃-C₇cycloalkyl substituted with oneor more substituents selected from the group consisting of halo andC₁-C₄alkyl; in particular R⁴ is selected from the group consisting ofHet¹ and C₃-C₇cycloalkyl substituted with one or more substituentsselected from the group consisting of halo and C₁-C₄alkyl; more inparticular R⁴ is Het¹.

In an embodiment, the present invention relates to those compounds offormula (I), or any subgroup thereof as mentioned in any of the otherembodiments, wherein R⁴ is selected from the group consisting oftert-butyl, aryl, Het² and CH(CH₃)(CF₃); in particular R⁴ is aryl orHet²; more in particular R⁴ is Het².

In an embodiment, the present invention relates to those compounds offormula (I), or any subgroup thereof as mentioned in any of the otherembodiments, wherein Z is C or N; R⁵ is present where Z is C, whereby R⁵is selected form the group consisting of CF₃ and halogen; R⁵ is absentwhere Z is N.

In an embodiment, the present invention relates to those compounds offormula (I), or any subgroup thereof as mentioned in any of the otherembodiments, wherein each R^(1c) is selected independently from thegroup consisting of H, halogen, C₁-C₆alkyloxy, CF₃, and OCF₃.

In an embodiment, the present invention relates to those compounds offormula (I), or any subgroup thereof as mentioned in any of the otherembodiments, wherein Het has formula (c) wherein each R^(1c) is selectedindependently from the group consisting of H, halogen, C₁-C₆alkyloxy,CF₃, and OCF₃.

In an embodiment, the present invention relates to those compounds offormula (I), or any subgroup thereof as mentioned in any of the otherembodiments, wherein R^(1c) in the para position to N—R^(2c) is selectedfrom the group consisting of H, halogen and all other R^(1c) are H. Inpreferred embodiment, halogen is bromo or chloro.

In an embodiment, the present invention relates to those compounds offormula (I), or any subgroup thereof as mentioned in any of the otherembodiments, wherein Het has formula (c) wherein R^(1c) in the paraposition to N—R^(2c) is selected from the group consisting of H, halogenand all other R^(1c) are H. In preferred embodiment, halogen is bromo orchloro.

In an embodiment, the present invention relates to those compounds offormula (I), or any subgroup thereof as mentioned in any of the otherembodiments, wherein Het has formula (c) wherein R^(2c) comprises a—(CR⁸R⁹)_(m) chain wherein R⁸ and R⁹ are H and m is 2-4. PreferablyR^(10c) is selected from the group consisting of OH, F, CF₂H, CF₃,SO₂R₈, and CN. R⁸ preferably is methyl.

In an embodiment, the present invention relates to those compounds offormula (I), or any subgroup thereof as mentioned in any of the otherembodiments, wherein R^(2c) comprises a —(CR⁸R⁹)_(m) chain wherein R⁸and R⁹ are H and m is 2-4. Preferably R^(10c) is selected from the groupconsisting of OH, F, CF₂H, CF₃, SO₂R₈, and CN. R⁸ preferably is methyl.

In an embodiment, the present invention relates to those compounds offormula (I), or any subgroup thereof as mentioned in any of the otherembodiments, wherein R⁴ is C₃-C₇cycloalkyl substituted with one or moresubstituents selected from the group consisting of halo and C₁-C₄alkyl;more preferably cyclopropyl substituted with halo or C₁-C₄alkyl.

In an embodiment, the present invention relates to those compounds offormula (I), or any subgroup thereof as mentioned in any of the otherembodiments, wherein Z is N.

In an embodiment, the present invention relates to those compounds offormula (I), or any subgroup thereof as mentioned in any of the otherembodiments, wherein R⁵ is H.

In an embodiment, the present invention relates to those compounds offormula (I), or any subgroup thereof as mentioned in any of the otherembodiments, wherein R⁴ is selected from the group consisting oftert-butyl, Het¹, aryl, Het² and C₃-C₇cycloalkyl substituted with one ormore substituents selected from the group consisting of halo andC₁-C₄alkyl;

-   R^(10b) is selected from the group consisting of H, C₁-C₆alkyl, OH,    CN, F, CF₂H, CF₃, CONR⁸R⁹, COOR⁸, CON(R⁸)SO₂R⁹, CON(R⁸)SO₂N(R⁸R⁹),    NR⁸R⁹, NR⁸COOR⁹, OCOR⁸, O-Benzyl, NR⁸SO₂R⁹, SO₂NR⁸R⁹, SO₂R⁸ and a 4    to 6 membered saturated ring containing one oxygen atom; and-   m is an integer from 2 to 6.

In an embodiment, the present invention relates to those compounds offormula (I), or any subgroup thereof as mentioned in any of the otherembodiments, wherein R^(10b) is selected from the group consisting of H,C₁-C₆alkyl, OH, CN, F, CF₂H, CF₃, CONR⁸R⁹, COOR⁸, CON(R⁸)SO₂R⁹,CON(R⁸)SO₂N(R⁸R⁹), NR⁸R⁹, NR⁸COOR⁹, OCOR⁸, O-Benzyl, NR⁸SO₂R⁹, SO₂NR⁸R⁹,SO₂R⁸ and a 4 to 6 membered saturated ring containing one oxygen atom.

In an embodiment, the present invention relates to those compounds offormula (I), or any subgroup thereof as mentioned in any of the otherembodiments, wherein Het has formula (b) wherein R^(10b) is selectedfrom the group consisting of H, C₁-C₆alkyl, OH, CN, F, CF₂H, CF₃,CONR⁸R⁹, COOR⁸, CON(R⁸)SO₂R⁹, CON(R⁸)SO₂N(R⁸R⁹), NR⁸R⁹, NR⁸COOR⁹, OCOR⁸,O-Benzyl, NR⁸SO₂R⁹, SO₂NR⁸R⁹, SO₂R⁸ and a 4 to 6 membered saturated ringcontaining one oxygen atom.

In an embodiment, the present invention relates to those compounds offormula (I), or any subgroup thereof as mentioned in any of the otherembodiments, wherein Het has formula (b) wherein at most two X are N. Ina preferred embodiment, one X is N. In a more preferred embodiment, theone X that is N is located in meta position to the N—R^(2b) group of theimidazole ring.

In an embodiment, the present invention relates to those compounds offormula (I), or any subgroup thereof as mentioned in any of the otherembodiments, wherein Het having formula (b) has at most two X being N.In a preferred embodiment, one X is N. In a more preferred embodiment,the one X that is N is located in meta position to the N—R^(2b) group ofthe imidazole ring.

In an embodiment, the present invention relates to those compounds offormula (I), or any subgroup thereof as mentioned in any of the otherembodiments, wherein each R^(1b) is selected independently from thegroup consisting of H, halogen and CH₂—NH₂. In a further preferredembodiment, R^(1b) in the para position to C—N—R^(2b) is selected fromthe group consisting of H, halogen and CH₂—NH₂, and all other R^(1b) areH. In a further preferred embodiment said halogen is bromo or chloro. Ina most preferred embodiment, at most one R^(1b) is chloro, and all otherR^(1b) are H. In yet an even more preferred embodiment, R^(1b) in thepara position to C—N—R^(2b) is chloro.

In an embodiment, the present invention relates to those compounds offormula (I), or any subgroup thereof as mentioned in any of the otherembodiments, wherein Het has formula (b) wherein each R^(1b) is selectedindependently from the group consisting of H, halogen and CH₂—NH₂. In afurther preferred embodiment, R^(1b) in the para position to C—N—R^(2b)is selected from the group consisting of H, halogen and CH₂—NH₂, and allother R^(1b) are H. In a further preferred embodiment said halogen isbromo or chloro. In a most preferred embodiment, at most one R^(1b) ischloro, and all other R^(1b) are H. In yet an even more preferredembodiment, R^(1b) in the para position to C—N—R^(2b) is chloro.

In an embodiment, the present invention relates to those compounds offormula (I), or any subgroup thereof as mentioned in any of the otherembodiments, wherein R¹¹ is C₁-C₆alkyl or C₃-C₇cycloalkyl; in particularC₁-C₆alkyl.

In an embodiment, the present invention relates to those compounds offormula (I), or any subgroup thereof as mentioned in any of the otherembodiments, wherein R^(2b) comprises a —(CR⁸R⁹)_(m)—R^(10b) chainwherein R⁸ and R⁹ are preferably H and m is 2-4. Preferably R^(10b) isselected from the group consisting of OH, C₁-C₆alkyl; more preferably2-propyl. Also preferably R^(10b) is selected from the group consistingof methoxy, SO₂R⁸, with R⁸ preferably being methyl. Most preferablyR^(10b) is fluoro or CF₃.

In an embodiment, the present invention relates to those compounds offormula (I), or any subgroup thereof as mentioned in any of the otherembodiments, wherein Het has formula (b) wherein R^(2b) comprises a—(CR⁸R⁹)_(m)—R^(10b) chain wherein R⁸ and R⁹ are preferably H and m is2-4. Preferably R^(10b) is selected from the group consisting of OH,C₁-C₆alkyl; more preferably 2-propyl. Also preferably R^(10b) isselected from the group consisting of methoxy, SO₂R⁸, with R⁸ preferablybeing methyl. Most preferably R^(10b) is fluoro or CF₃.

In an embodiment, the present invention relates to those compounds offormula (I), or any subgroup thereof as mentioned in any of the otherembodiments, wherein R⁴ is selected from C₃-C₇cycloalkyl substitutedwith one or more substituents selected from the group consisting of haloand C₁-C₄alkyl.

In an embodiment, the present invention relates to those compounds offormula (I), or any subgroup thereof as mentioned in any of the otherembodiments, wherein R⁴ is selected from the group consisting of Het¹and cyclopropyl substituted with halo or C₁-C₄alkyl.

In an embodiment, the present invention relates to those compounds offormula (I), or any subgroup thereof as mentioned in any of the otherembodiments, wherein R⁵ is halogen, in particular fluoro.

In an embodiment, the present invention relates to those compounds offormula (I), or any subgroup thereof as mentioned in any of the otherembodiments, wherein each R^(1d) independently is selected from thegroup of H, halogen, C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, N(R⁶)₂,CO(R⁶), CH₂NH₂, CH₂OH, CN, C(═NOH)NH₂, C(═NOCH₃)NH₂, C(═NH)NH₂, CF₃,OCF₃, B(OH)₂ and B(O—C₁-C₆alkyl)₂.

In an embodiment, the present invention relates to those compounds offormula (I), or any subgroup thereof as mentioned in any of the otherembodiments, wherein Het has formula (d) wherein each R^(1d)independently is selected from the group of H, halogen, C₁-C₆alkyl,C₃-C₇cycloalkyl, C₁-C₆alkyloxy, N(R⁶)₂, CO(R⁶), CH₂NH₂, CH₂OH, CN,C(═NOH)NH₂, C(═NOCH₃)NH₂, C(═NH)NH₂, CF₃, OCF₃, B(OH)₂ andB(O—C₁-C₆alkyl)₂.

In an embodiment, the present invention relates to those compounds offormula (I), or any subgroup thereof as mentioned in any of the otherembodiments, wherein Het has formula (d) wherein at most two X are N. Ina preferred embodiment, one X is N. In a more preferred embodiment, theone X that is N is located is in meta or para position to the N—R^(2d).In a further preferred embodiment, X is in the position para toN—R^(2d).

In an embodiment, the present invention relates to those compounds offormula (I), or any subgroup thereof as mentioned in any of the otherembodiments, wherein Het having formula (d) has at most two X being N.In a preferred embodiment, one X is N. In a more preferred embodiment,the one X that is N is located is in meta or para position to theN—R^(2d). In a further preferred embodiment, X is in the position parato N—R^(2d).

In an embodiment, the present invention relates to those compounds offormula (I), or any subgroup thereof as mentioned in any of the otherembodiments, wherein each R^(1d) is selected independently from thegroup consisting of H or halogen. In a further preferred embodiment,R^(1d) in the para position to N—R^(2d) is halogen, and all other R^(1d)are H. In a further preferred embodiment said halogen is bromo orchloro. In a most preferred embodiment, said halogen is chloro.

In an embodiment, the present invention relates to those compounds offormula (I), or any subgroup thereof as mentioned in any of the otherembodiments, wherein Het has formula (d) wherein each R^(1d) is selectedindependently from the group consisting of H or halogen. In a furtherpreferred embodiment, R^(1d) in the para position to N—R^(2d) ishalogen, and all other R^(1d) are H. In a further preferred embodimentsaid halogen is bromo or chloro. In a most preferred embodiment, saidhalogen is chloro.

In an embodiment, the present invention relates to those compounds offormula (I), or any subgroup thereof as mentioned in any of the otherembodiments, wherein R^(2d) comprises a —(CR⁸R⁹)_(m) chain wherein R⁸and R⁹ are preferably H and m is 2-4. Preferably R^(10d) is selectedfrom the group consisting of OH, F, CF₃, CF₂H and C₁-C₆alkyl; inparticular 2-propyl.

In an embodiment, the present invention relates to those compounds offormula (I), or any subgroup thereof as mentioned in any of the otherembodiments, wherein Het has formula (d) wherein R^(2d) comprises a—(CR⁸R⁹)_(m) chain wherein R⁸ and R⁹ are preferably H and m is 2-4.Preferably R^(10d) is selected from the group consisting of OH, F, CF₃,CF₂H and C₁-C₆alkyl; in particular 2-propyl.

In an embodiment, the present invention relates to those compounds offormula (I), or any subgroup thereof as mentioned in any of the otherembodiments, wherein Het has formula (e) wherein R^(3e) is selected fromthe group consisting of H, halogen, —(CR⁸R⁹)_(m)—R^(10e),C≡C—CH₂—R^(10e) and C≡C—R^(10e).

In an embodiment, the present invention relates to those compounds offormula (I), or any subgroup thereof as mentioned in any of the otherembodiments, wherein R^(3e) is selected from the group consisting of H,halogen, —(CR⁸R⁹)_(m)—R^(10e), C≡C—CH₂—R^(10e) and C≡C—R^(10e).

In an embodiment, the present invention relates to those compounds offormula (I), or any subgroup thereof as mentioned in any of the otherembodiments, wherein Het has formula (e) wherein Y is C.

In an embodiment, the present invention relates to those compounds offormula (I), or any subgroup thereof as mentioned in any of the otherembodiments, wherein Y is C.

In an embodiment, the present invention relates to those compounds offormula (I), or any subgroup thereof as mentioned in any of the otherembodiments, wherein Het having formula (e) is limited to formula (e1)

In an embodiment, the present invention relates to those compounds offormula (I), or any subgroup thereof as mentioned in any of the otherembodiments, wherein all substituents R^(1e) are H.

In an embodiment, the present invention relates to those compounds offormula (I), or any subgroup thereof as mentioned in any of the otherembodiments, wherein Het has formula (e) wherein all substituents R^(1e)are H.

In an embodiment, the present invention relates to those compounds offormula (I), or any subgroup thereof as mentioned in any of the otherembodiments, wherein at least one of R^(1e) is halogen, more preferablyCl or Br.

In an embodiment, the present invention relates to those compounds offormula (I), or any subgroup thereof as mentioned in any of the otherembodiments, wherein Het has formula (e) wherein at least one of R^(1e)is halogen, more preferably Cl or Br.

In an embodiment, the present invention relates to those compounds offormula (I), or any subgroup thereof as mentioned in any of the otherembodiments, wherein m comprises a carbon chain of 2-6 atoms, inparticular 2-4 atoms, more in particular 3-5 atoms.

In an embodiment, the present invention relates to those compounds offormula (I), or any subgroup thereof as mentioned in any of the otherembodiments, wherein R^(10e) is selected from the group consisting ofOH, C₁-C₆alkyloxy, secondary C₁-C₆alkyl; in particular OH or 2-propyl.“Secondary C₁-C₆alkyl” is intended to refer to an alkyl moiety that isattached via a non-terminal carbon atom, e.g. 2-propyl, 3-pentyl, andthe like.

In an embodiment, the present invention relates to those compounds offormula (I), or any subgroup thereof as mentioned in any of the otherembodiments, wherein Het has formula (e) wherein R^(10e) is selectedfrom the group consisting of OH, C₁-C₆alkyloxy, secondary C₁-C₆alkyl; inparticular OH or 2-propyl. “Secondary C₁-C₆alkyl” is intended to referto an alkyl moiety that is attached via a non-terminal carbon atom, e.g.2-propyl, 3-pentyl, and the like.

In an embodiment, the present invention relates to those compounds offormula (I), or any subgroup thereof as mentioned in any of the otherembodiments, wherein R^(3e) is C≡C—CH₂—R^(10e). Herein R^(10e)preferably is C₁-C₆alkyloxy, preferably methoxy, or C₁-C₆alkyl,preferably branched alkyl.

In an embodiment, the present invention relates to those compounds offormula (I), or any subgroup thereof as mentioned in any of the otherembodiments, wherein Het has formula (e) wherein R^(3e) isC≡C—CH₂—R^(10e). Herein R^(10e) preferably is C₁-C₆alkyloxy, preferablymethoxy, or C₁-C₆alkyl, preferably branched alkyl.

Interesting compounds of formula (I) are those compounds of formula (I)wherein one or more of the following restrictions apply:

-   a) Het is a heterocycle having formula (b), (d) or (e);-   b) Het is a heterocycle having formula (b),-   c) Het is a heterocycle having formula (c);-   d) Het is a heterocycle having formula (d);-   e) Z is N and R⁵ is absent;-   f) Z is C and R⁵ is halogen;-   g) R⁴ is selected from the group consisting of Het % aryl, Het², and    C₃-C₇cycloalkyl substituted with one or more substituents selected    from the group consisting of halo and C₁-C₄alkyl;-   h) R⁴ is Het¹;-   i) R⁴ is Het²;-   j) R⁴ is aryl;-   k) aryl is phenyl optionally being substituted with one or more    substituents each independently selected from the group consisting    of halo, C₁-C₄alkyloxy, CN, CONR⁸R⁹, COOR⁸, SO₂R⁸,    polyhaloC₁₋₄alkyloxy or C₁₋₄alkyloxy C₁₋₄alkyloxy;-   l) aryl is phenyl optionally being substituted with one or more    substituents each independently selected from the group consisting    of halo, C₁-C₄alkyloxy, CN, CONR⁸R⁹, COOR⁸, SO₂R⁸;-   m) aryl is phenyl substituted with two substituents each    independently selected from the group consisting of halo,    C₁-C₄alkyloxy or C₁-C₄alkyl;-   n) Het is a heterocycle having formula (c-1a) wherein R^(1c) is H    and R^(2c)-    is —(CR⁸R⁹)_(m)—R^(10c) wherein R⁸ and R⁹ are each H, m is 3 and    R^(10c) represents CN or SO₂CH₃.

General Synthetic Schemes

The compounds of formula I may be prepared by the methods describedbelow, using synthetic methods known in the art of organic chemistry, ormodifications and derivatisations that are familiar to those skilled inthe art. The starting materials used herein are commercially availableor may be prepared by routine methods known in the art such as thosemethods disclosed in standard reference books. Preferred methodsinclude, but are not limited to, those described below.

During any of the following synthetic sequences it may be necessaryand/or desirable to protect sensitive or reactive groups on any of themolecules concerned. This can be achieved by means of conventionalprotecting groups, such as those described in T. W. Greene and P. G. M.Wuts, Protective Groups in Organic Chemistry, John Wiley & Sons, 1999,which are hereby incorporated by reference.

Compounds of formula I, or their pharmaceutically acceptable salts, canbe prepared according to the reaction schemes discussed herein below.Unless otherwise indicated, the substituent in the schemes are definedas above. Isolation and purification of the products is accomplished bystandard procedures, which are known to a chemist of ordinary skill.

Scheme 1 illustrates a method for the preparation of compounds offormula (I), wherein Het is a heterocycle of formula (b), hereby named acompound of formula I-b where R^(1b), R^(2b), R⁴, R⁵ and Z are definedas above.

Referring to scheme 1, a compound of formula I-b can be synthesized bycoupling 2-hydroxymethylene imidazopyridines of formula II-a with aN³-substituted 2-oxo-imidazopyridine or with a N³-substituted2-oxo-imidazobenzene of formula III in a known in the art method such asa Mitsunobu reaction which uses azadiisopropyldicarboxylate andtriphenyl phosphine in a suitable solvent such as DMF(N,N-dimethylformamide) or THF (tetrahydrofuran). Alternatively, acompound of formula I-b may be prepared by displacement of Q, which is ahalide, preferably chlorine II-b, or a sulfonate such as mesylate II-cin the presence of a base such as sodium hydride, potassium carbonate orcesium carbonate in a suitable solvent such as DMF or THF.

Preparation of Intermediates II-b and II-c

Treatment of the alcohol II-a with thionyl chloride provides2-chloromethyl imidazopyridines II-b. Alternatively, alcohol II-a may betransformed to the intermediate II-c by a reaction with methane sulfonylchloride in the presence of an organic base such as triethyl amine ordiisopropyl ethyl amine in a suitable solvent such as dichloromethane(scheme 2).

Preparation of Intermediate II-a

Intermediates of formula II-a are either commercially available or canbe prepared, but not limited to, by general procedures illustrated byscheme 3, wherein R^(1b), R^(2b), X are defined as above. Referring toscheme 3 below, haloheteroaryls IV-b, where W is an halide preferablyfluorine, can be treated with primary amines of formula V-b in thepresence of a suitable base such as potassium carbonate and the like, ina suitable solvent such as ethanol or dichloromethane at a reactiontemperature ranging from room temperature to 100° C. to giveintermediates of formula VI-b. Hydrogenation of the nitro group usingwell-precedented conditions such as Pd/C, or other catalyst, underhydrogen or Fe/EtOH/CaCl₂ can yield diamine of formula VII-b.Alternatively, the hydrogenation of the nitro group of intermediateVIII-b using well-precedented conditions such as Pd/C, or othercatalyst, under hydrogen or Fe/EtOH/CaCl₂ yield diamine of formula IX-bwhich can be treated with the aldehydes of formula X-b in the presenceof suitable reducing agents such as NaBH(OAc)₃ (sodiumtriacetoxyborohydride), or Na(CN)BH₃ in solvents such as methylenechloride, DMF or THF, at about room temperature gives compounds offormula VII-b. The imidazole ring can be formed by treating diaminesVII-b with glycolic acid or an ester like XIII-b under strong acidicconditions, such as aqueous hydrochloric acid, at elevated temperaturesuch as reflux to yield the alcohols of formula II-a. Alternatively,diamines VII-b can be condensed with dialkoxyacetate of formula XII-b,in the presence of acetic acid, in a suitable solvent such as methanolgives the acetal II-e. The acetal of compounds II-e can be removed withacids such as hydrochloric acid to give the aldehydes of formula II-f.The resulting aldehydes of formula II-f can be reduced to alcohols usinga suitable reducing agent such as NaBH₄ or LiAlH₄ in a suitable solventsuch as ethanol or THF to yield the desired alcohols of formula II-a. Inaddition, diamines VII-b can be cyclize with dialkyl oxalate of formulaXI-b in a suitable solvent such as ethanol at elevated temperature withor without microwave heating to produce imidazoles of formula II-d.Alternatively, intermediates of formula II-d may be prepared in twosteps synthesis starting from diamines VII-b. Firstly diamine VII-b maybe reacted with an alkyl trihaloacetimidate, preferably methyl2,2,2-trichloro-acetimidate, in an acidic media, preferably acetic acid,at a temperature ranging between 25 and 50° C. to yield compound offormula II-g. Secondly a reaction of compounds of formula II-g withmetalcarbonate, preferably sodium carbonate in a suitable solvent suchas methanol, lead to intermediates of formula II-d. Intermediates offormula II-d may subsequently be reduced to the desired alcohols offormula II-a using a suitable reducing agent such as NaBH₄ or LiAlH₄ ina suitable solvent such as ethanol or THF.

An alternative route for the preparation of intermediates of type II-ais depicted in scheme 4. Diamine IX-b may be first coupled to an alkylglycolic acid or an ester like XIII-b under strong acidic conditions,such as aqueous hydrochloric acid, at elevated temperature such asreflux to yield the alcohols of formula XIV-b. This alcohol may beprotected by a PG, where PG is a protecting group such as, but notlimiting to, a trityl which consequently results in intermediates offormula XV-b. A suitable solvent for this type of reactions can be, butnot limiting to, dichloromethane. The treatment of intermediate XV-bwith intermediate XVI-b, wherein the LG is a leaving group, such ashalide, preferably bromine, or sulfonate, in the presence of a base suchas sodium hydride, potassium carbonate or cesium carbonate in a suitablesolvent such as DMF or THF, gives intermediate II-h. The removal of thePG in intermediate II-h may be done in the presence of an acid such ashydrochloric acid in the presence of a solvent, not limited to, such asdioxane to yield an intermediate of formula II-a.

The Synthesis of a 2-oxo-imidazopyridine and a 2-oxo-imidazobenzene offormula III is shown in scheme 5. Intermediates of formula III can besynthesized using the procedure depicted in scheme 5. Displacement of W,which is a halide, preferably fluorine, or an alkoxy group, preferablymethoxy, of nitro pyridine or of nitro aryl XVII with an amine, in asuitable solvent such as THF or DMF, in the presence of an organic basesuch as triethyl amine or diisopropyl ethyl amine, gives an intermediateof formula XVIII. Reduction of the nitro group to the amine XIX can bedone in a catalytic way using hydrogen in the presence of a catalystsuch as palladium or platinum, in a suitable solvent such as methanol,or in a stoichiometric way using iron in the presence of ammoniumchloride or tin chloride in the presence of concentrated hydrochloricacid. The cyclisation of the resulting diamine XIX using1,1′-carbonyldiimidazole (CDI), phosgene or triphosgene, in a solventsuch as acetonitrile or THF, provides a N³-substituted2-oxo-imidazopyridine or a N³-substituted 2-oxo-imidazobenzenederivative of formula III. Alternatively, an intermediate of type IIImay be prepared starting from commercially available dianilines XX whichcan be cyclized by ring closure with CDI, phosgene or triphosgene yieldsintermediates of type XXI. Introduction of a R⁴ substituent (other thanH) on an intermediate of formula XXI can be accomplished by a Mitsunobureaction with commercially available alcohols, or by displacement of theLG in the intermediates of formula XXII, where LG is a leaving groupsuch as halide, preferably bromine, or sulfonate, in the presence of abase such as sodium hydride, potassium carbonate or cesium carbonate ina suitable solvent such as DMF or THF. This will finally yieldintermediates of formula III.

Scheme 6 illustrates a method for the preparation of compounds offormula (I), wherein Het is a heterocycle of formula (c), hereby named acompound of formula I-c, where R^(1c), R^(2c), R^(3c), R⁴, R⁵ and Z aredefined as above.

Referring to scheme 6, a compound of formula I-c can be synthesized bycoupling a 2-hydroxymethylene indole of formula II-i with aN³-substituted 2-oxo-imidazopyridine or with a N³-substituted2-oxo-imidazobenzene of formula III with a method known in the artmethod such as a Mitsunobu reaction which usesazadiisopropyldicarboxylate and triphenyl phosphine in a suitablesolvent such as DMF or THF. Alternatively, a compound of formula I-c maybe prepared by displacement of Y, which is a halide, preferably chlorineII-j, or a sulfonate such as mesylate II-k in the presence of a basesuch as sodium hydride, potassium carbonate or cesium carbonate in asuitable solvent such as DMF or THF.

Preparation of Compound II-i

Starting materials IV-c used in this invention are commerciallyavailable, or can be synthesized, but not limited to, by methods knownin the art such as Reissert synthesis or Fischer synthesis. Reaction ofsuch indoles with R^(2c)-LG, where LG is a leaving group such as halide,preferably bromine, or sulfonate, in the presence of a base such assodium hydride, potassium carbonate or cesium carbonate in a suitablesolvent such as DMF or THF, gives intermediates V-c (scheme 7). Theconversion of the alkyl ester of an intermediate of formula V-c to thealcohol II-i may be carried out with metal hydride such as lithiumaluminum hydride or sodium borohydride in a suitable solvent such asTHF, methanol or ethanol.

Alternatively, starting materials VI-c can be synthesized, but notlimited to, by methods known in the art such as Reissert synthesis orFischer synthesis. Reaction of such indoles with R^(2c)-LG, where LG isa leaving group such as halide, preferably bromine, or sulfonate, in thepresence of a base such as sodium hydride, potassium carbonate or cesiumcarbonate in a suitable solvent such as DMF or THF, gives intermediatesof formula VII-c. The oxidation of the methyl with selenium oxide ormanganese dioxide in a suitable solvent such as dichloromethane orheptane leads to the aldehyde VIII-c. The conversion of the aldehydeVIII-c to the alcohol II-i may be carried out with metal hydride such aslithium aluminum hydride or sodium borohydride in a suitable solventsuch as THF, methanol or ethanol.

Treatment of the alcohol II-i with thionyl chloride provides2-chloromethyl indole II-j. Alternatively, alcohol II-i may betransformed to the intermediate II-k by a reaction with methane sulfonylchloride in the presence of an organic base such as triethyl amine ordiisopropyl ethyl amine in a suitable solvent such dichloromethane(scheme 8).

Scheme 9 illustrates a method for the preparation of compounds offormula I-d, where R^(1d), R^(2d), R^(3d), R⁴, R⁵ and Z are defined asabove.

A compound of formula I-d can be synthesized by coupling2-hydroxymethylene indole II-l with a benzimidazolone III in a known inthe art method such as Mitsunobu reaction which usesazadiisopropyldicarboxylate (DIAD) and triphenylphosphine in a suitablesolvent such as DMF or THF. Alternatively, compounds of formula I-d maybe prepared by displacement of Q, which is a halide, preferably chlorineII-m, or sulfonate such as mesylate II-n in the presence of a base suchas, but not limiting to, sodium hydride, potassium carbonate or cesiumcarbonate in a suitable solvent such as DMF or THF.

An intermediate of formula II-l is prepared according to the methods asdepicted in scheme 10.

Starting materials IV-d used in this invention, according to method 1,are commercially available, or can be synthesized, but not limited to,by methods known in the art such as Reissert synthesis or Fischersynthesis. Reaction of such an intermediate with R^(2d)-LG, where LG isa leaving group such as halide, preferably bromine, or sulfonate, in thepresence of a base such as sodium hydride, potassium carbonate or cesiumcarbonate in a suitable solvent such as DMF or THF, gives anintermediate of formula V-d. The conversion of the alkyl ester ofintermediate V-d to the alcohol II-l can be done with a metal hydridesuch as lithium aluminum hydride or sodium borohydride in a suitablesolvent such as THF or methanol.

Alternatively a II-l type intermediate can also be synthesized as shownin scheme 10, method 2. The commercially available starting materialVI-d is protected by a PG, where PG is a protecting group such as, butnot limiting to, a tosyl, which consequently results in an intermediateof formula VII-d. A suitable solvent for this kind of reactions can be,but not limiting to, toluene. The metallation of intermediate VII-dfollowed by treatment with compound carbon dioxide, in a suitablesolvent such as, but not limited to, THF, yields intermediate IX-d. Theesterification of acid in the intermediate IX-d can be performed withalcohols such methanol or ethanol in acidic conditions to yieldintermediate X-d. The removal of the PG in intermediate X-d may be donein the presence of a base such as potassium carbonate or cesiumcarbonate in a suitable solvent such as THF and methanol to obtainindole XI-d. Reaction of indoles XI-d with R^(2d)-LG, where LG is aleaving group such as a halide, preferably bromine, or sulfonate, in thepresence of a base such as sodium hydride, potassium carbonate or cesiumcarbonate in a suitable solvent such as DMF or THF, gives intermediateXII-d. The conversion of the alkyl ester of intermediate XII-d to thealcohol II-l can be carried out with a metal hydride such as lithiumaluminium hydride or sodium borohydride in a suitable solvent such asTHF or ethanol.

Treatment of the alcohol II-l with reagents like, but not limiting to,SOCl₂, PBr₃, p-TsCl (4-toluenesulfonyl chloride) or MsCl(methanesulfonyl chloride), provides 2-chloromethyl indole derivativesII-m or intermediates like II-n.

Scheme 12 illustrates a method for the preparation of compounds offormula I-e, where R^(1c), R^(3e), R⁴, R⁵, R^(10e), Q, Y and Z aredefined as above.

A IV-e type compound can be made by coupling 2-hydroxymethyleneimidazopyridine II-o with a N³-substituted benzimidazolone III in aknown in the art method such as Mitsunobu reaction which use theazadiisopropyldicarboxylate and triphenylphosphine in a suitable solventsuch as, but not limiting to, DMF or THF. Alternatively, compounds offormula I-e may be prepared by displacement of Q, which is a halide,II-p, preferably chlorine, or sulfonate, II-q, such as mesylate ortosylate, in the presence of base such as, but not limiting to, sodiumhydride, potassium carbonate or cesium carbonate in a suitable solventsuch as DMF or THF. Halogenating reagents such as, but not limited to,N-iodosuccinimide can be used to convert a IV-e type intermediate to aV-e type intermediate and CH₃CN can be a suitable solvent for thisreaction. By coupling an alkyn to a V-e type intermediate in a known inthe art method such as Sonogashira-type coupling reaction, a VI-e typeintermediate can be generated. Reduction of the triple bond can be donein a catalytic way using hydrogen in the presence of the catalyst suchas palladium or platinum, in a suitable solvent such as methanol, or ina stoichiometric way using iron in the presence of ammoniumchloride ortin chloride in the presence of concentrated hydrochloric acid to yielda compound of formula I-e.

The synthesis of II-o type intermediates can generally be prepared asdepicted in scheme 13. A IX-e type intermediate can be synthesized bycoupling a commercially available VII-e type intermediate with acommercially available VIII-e type intermediate, of which the halogen ispreferably bromine, through a base mediated coupling reaction. Possiblebases to effect this reaction, but not limiting to, are K₂CO₃, Cs₂CO₃,triethylamine and sodium hydride. A suitable solvent for this type ofbase mediated coupling is DME (1,2-dimethoxyethane). After an intramolecular ring closure by thermal heating, an intermediate of formulaX-e can be generated. The conversion of the alkyl ester of intermediateX-e to the alcohol II-o was carried out with metal hydride such aslithium aluminium hydride or sodium borohydride in a suitable solventsuch as THF or methanol.

Scheme 14 shows the possibilities to synthesize II-p and II-q typeintermediates. Treatment of the alcohol II-o with reagents like, but notlimiting to, SOCl₂, PBr₃, p-TsCl (4-toluenesulfonyl chloride), MsCl(methane sulfonyl chloride) provides 2-chloromethyl indole II-p and tothe intermediate II-q in the presence of an organic base, such astriethylamine or diisopropylethylamine in a suitable solvent such asdichloromethane. This is illustrated by method 1.

Alternatively a II-p type compound can also be generated through aninter molecular ring closure between a commercially available XI-e typecompound and an also commercially available XII-e type compound. Asuitable solvent for this reaction can be ethanol. This is illustratedby method 2.

Pure stereochemically isomeric forms of the compounds of formula (I) maybe obtained by the application of art-known procedures. Diastereomersmay be separated by physical methods such as selective crystallizationand chromatographic techniques, e.g., counter-current distribution,liquid chromatography and the like.

The compounds of formula (I) as prepared in the hereinabove describedprocesses are generally racemic mixtures of enantiomers which can beseparated from one another following art-known resolution procedures.The racemic compounds of formula (I) which are sufficiently basic oracidic may be converted into the corresponding diastereomeric salt formsby reaction with a suitable chiral acid, respectively chiral base. Saiddiastereomeric salt forms are subsequently separated, for example, byselective or fractional crystallization and the enantiomers areliberated therefrom by alkali or acid. An alternative manner ofseparating the enantiomeric forms of the compounds of formula (I)involves liquid chromatography, in particular liquid chromatographyusing a chiral stationary phase. Said pure stereochemically isomericforms may also be derived from the corresponding pure stereochemicallyisomeric forms of the appropriate starting materials, provided that thereaction occurs stereospecifically. Preferably if a specificstereoisomer is desired, said compound will be synthesized bystereospecific methods of preparation. These methods will advantageouslyemploy enantiomerically pure starting materials.

In a further aspect, the present invention concerns a pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof formula (I) as specified herein, or a compound of any of theembodiments of compounds of formula (I) as specified herein, and apharmaceutically acceptable carrier. A therapeutically effective amountin this context is an amount sufficient to prophylaxictically actagainst, to stabilize or to reduce viral infection, and in particularRSV viral infection, in infected subjects or subjects being at risk ofbeing infected. In still a further aspect, this invention relates to aprocess of preparing a pharmaceutical composition as specified herein,which comprises intimately mixing a pharmaceutically acceptable carrierwith a therapeutically effective amount of a compound of formula (I), asspecified herein, or of a compound of any of the embodiments ofcompounds of formula (I) as specified herein.

Therefore, the compounds of the present invention or any embodimentthereof may be formulated into various pharmaceutical forms foradministration purposes. As appropriate compositions there may be citedall compositions usually employed for systemically administering drugs.To prepare the pharmaceutical compositions of this invention, aneffective amount of the particular compound, optionally in addition saltform, as the active ingredient is combined in intimate admixture with apharmaceutically acceptable carrier, which carrier may take a widevariety of forms depending on the form of preparation desired foradministration. These pharmaceutical compositions are desirable inunitary dosage form suitable, particularly, for administration orally,rectally, percutaneously, or by parenteral injection. For example, inpreparing the compositions in oral dosage form, any of the usualpharmaceutical media may be employed such as, for example, water,glycols, oils, alcohols and the like in the case of oral liquidpreparations such as suspensions, syrups, elixirs, emulsions andsolutions; or solid carriers such as starches, sugars, kaolin,lubricants, binders, disintegrating agents and the like in the case ofpowders, pills, capsules, and tablets. Because of their ease inadministration, tablets and capsules represent the most advantageousoral dosage unit forms, in which case solid pharmaceutical carriers areobviously employed. For parenteral compositions, the carrier willusually comprise sterile water, at least in large part, though otheringredients, for example, to aid solubility, may be included. Injectablesolutions, for example, may be prepared in which the carrier comprisessaline solution, glucose solution or a mixture of saline and glucosesolution. Injectable suspensions may also be prepared in which caseappropriate liquid carriers, suspending agents and the like may beemployed. Also included are solid form preparations which are intendedto be converted, shortly before use, to liquid form preparations. In thecompositions suitable for percutaneous administration, the carrieroptionally comprises a penetration enhancing agent and/or a suitablewetting agent, optionally combined with suitable additives of any naturein minor proportions, which additives do not introduce a significantdeleterious effect on the skin. The compounds of the present inventionmay also be administered via oral inhalation or insufflation by means ofmethods and formulations employed in the art for administration via thisway. Thus, in general the compounds of the present invention may beadministered to the lungs in the form of a solution, a suspension or adry powder, a solution being preferred. Any system developed for thedelivery of solutions, suspensions or dry powders via oral inhalation orinsufflation are suitable for the administration of the presentcompounds.

Thus, the present invention also provides a pharmaceutical compositionadapted for administration by inhalation or insufflation through themouth comprising a compound of formula (I) and a pharmaceuticallyacceptable carrier. Preferably, the compounds of the present inventionare administered via inhalation of a solution in nebulized oraerosolized doses.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in unit dosage form for ease ofadministration and uniformity of dosage. Unit dosage form as used hereinrefers to physically discrete units suitable as unitary dosages, eachunit containing a predetermined quantity of active ingredient calculatedto produce the desired therapeutic effect in association with therequired pharmaceutical carrier. Examples of such unit dosage forms aretablets (including scored or coated tablets), capsules, pills,suppositories, powder packets, wafers, injectable solutions orsuspensions and the like, and segregated multiples thereof.

The compounds of formula (I) show antiviral properties. Viral infectionstreatable using the compounds and methods of the present inventioninclude those infections brought on by ortho- and paramyxoviruses and inparticular by human and bovine respiratory syncytial virus (RSV). Anumber of the compounds of this invention moreover are active againstmutated strains of RSV. Additionally, many of the compounds of thisinvention show a favorable pharmacokinetic profile and have attractiveproperties in terms of bioavailabilty, including an acceptablehalf-life, AUC and peak values and lacking unfavourable phenomena suchas insufficient quick onset and tissue retention.

The in vitro antiviral activity against RSV of the present compounds wastested in a test as described in the experimental part of thedescription, and may also be demonstrated in a virus yield reductionassay. The in vivo antiviral activity against RSV of the presentcompounds may be demonstrated in a test model using cotton rats asdescribed in Wyde et al. (Antiviral Research (1998), 38, 31-42).

Due to their antiviral properties, particularly their anti-RSVproperties, the compounds of formula (I) or any embodiment thereof, andstereoisomeric forms thereof, and the pharmaceutically acceptableaddition salts, and the solvates thereof, are useful in the treatment ofindividuals experiencing a viral infection, particularly a RSVinfection, and for the prophylaxis of these infections. In general, thecompounds of the present invention may be useful in the treatment ofwarm-blooded animals infected with viruses, in particular therespiratory syncytial virus.

The compounds of the present invention or any embodiment thereof maytherefore be used as medicines. Said use as a medicine or method oftreatment comprises the systemic administration to viral infectedsubjects or to subjects susceptible to viral infections of an amounteffective to combat the conditions associated with the viral infection,in particular the RSV infection.

The present invention also relates to the use of the present compoundsor any embodiment thereof in the manufacture of a medicament for thetreatment or the prevention of viral infections, particularly RSVinfection.

The present invention furthermore relates to a method of treating awarm-blooded animal infected by a virus, or being at risk of infectionby a virus, in particular by RSV, said method comprising theadministration of an anti-virally effective amount of a compound offormula (I), as specified herein, or of a compound of any of theembodiments of compounds of formula (I), as specified herein.

In general it is contemplated that an antivirally effective daily amountwould be from 0.01 mg/kg to 500 mg/kg body weight, more preferably from0.1 mg/kg to 50 mg/kg body weight. It may be appropriate to administerthe required dose as two, three, four or more sub-doses at appropriateintervals throughout the day. Said sub-doses may be formulated as unitdosage forms, for example, containing 1 to 1000 mg, and in particular 5to 200 mg of active ingredient per unit dosage form.

The exact dosage and frequency of administration depends on theparticular compound of formula (I) used, the particular condition beingtreated, the severity of the condition being treated, the age, weight,sex, extent of disorder and general physical condition of the particularpatient as well as other medication the individual may be taking, as iswell known to those skilled in the art. Furthermore, it is evident thatsaid effective daily amount may be lowered or increased depending on theresponse of the treated subject and/or depending on the evaluation ofthe physician prescribing the compounds of the instant invention. Theeffective daily amount ranges mentioned hereinabove are therefore onlyguidelines.

Also, the combination of another antiviral agent and a compound offormula (I) can be used as a medicine. Thus, the present invention alsorelates to a product containing (a) a compound of formula (I), and (b)another antiviral compound, as a combined preparation for simultaneous,separate or sequential use in antiviral treatment. The different drugsmay be combined in a single preparation together with pharmaceuticallyacceptable carriers. For instance, the compounds of the presentinvention may be combined with interferon-beta or tumor necrosisfactor-alpha in order to treat or prevent RSV infections.

The invention will hereinafter be illustrated with reference to thefollowing, non-limiting examples.

EXPERIMENTAL PART

Hereinafter, the term ‘eq.’ means equivalent, ‘THF’ meanstetrahydrofuran, ‘Psi’ means pound-force per square inch, ‘DMF’ meansN,N-dimethylformamide, ‘DMSO’ means dimethyl sulfoxide, ‘DIEA’ meansdiisopropylethylamine, ‘DIAD’ means diisopropyl azodicarboxylate, ‘HOAc’or ‘AcOH’ means acetic acid, ‘RP’ means reversed phase, ‘EtOAc’ meansethyl acetate, ‘Pd(dppf)Cl₂CH₂Cl₂’ means[1,1′-bis(diphenylphosphino)ferrocene]palladium chloride complex withdichloro-methane, ‘TPP’ means triphenylphosphine, ‘m-cPBA’ means3-chlorobenzene-carboperoxoic acid, ‘Cu(OAc)₂’ means copper(II) acetate,‘EtOH’ means ethanol, ‘MeOH’ means methanol, ‘MeCN’ means methylcyanide, ‘CDT’ means 1,1′-carbonyldiimidazole, ‘KOEt’ means potassiumethoxide, and ‘HPLC’ means High Performance Liquid Chromatography.

LCMS (Liquid Chromatography/Mass spectrometry)

LCMS was done using either of the following methods:

General Method a

The LC measurement was performed using an Acquity UPLC (Waters) (‘UPLC’means Ultra Performance Liquid Chromatography) system comprising abinary pump, a sample organizer, a column heater (set at 55° C.), adiode-array detector (DAD) and a column as specified in the respectivemethods below. Flow from the column was split to a MS spectrometer. TheMS detector was configured with an electrospray ionization source. Massspectra were acquired by scanning from 100 to 1000 in 0.18 seconds usinga dwell time of 0.02 seconds. The capillary needle voltage was 3.5 kVand the source temperature was maintained at 140° C. Nitrogen was usedas the nebulizer gas. Data acquisition was performed with aWaters-Micromass MassLynx-Openlynx data system.

General Method B

The LC measurement was performed using an Acquity UPLC (Waters) systemcomprising a binary pump, a sample organizer, a column heater (set at55° C.), a diode-array detector (DAD) and a column as specified in therespective methods below. All the flow from the column went to a MSspectrometer. The MS detector was configured with an electrosprayionization source. Mass spectra were acquired by scanning from 120 to1000 in 0.1 seconds. The capillary needle voltage was 3.0 kV and thesource temperature was maintained at 150° C. Nitrogen was used as thenebulizer gas. Data acquisition was performed with a Waters-MicromassMassLynx-Openlynx data system.

Method 1

In addition to the general method A: Reversed phase UPLC was carried outon a bridged ethylsiloxane/silica hybrid (BEH) C18 column (1.7 μm,2.1×50 mm; Waters Acquity) with a flow rate of 0.8 ml/min. Two mobilephases (10 mM ammonium acetate in H₂O/acetonitrile 95/5; mobile phase B:acetonitrile) were used to run a gradient condition from 95% A and 5% Bto 5% A and 95% B in 1.3 minutes and hold for 0.3 minutes. An injectionvolume of 0.5 μl was used. Cone voltage was 10 V for positive ionizationmode and 20 V for negative ionization mode.

Method 2

In addition to the general method B: Reversed phase UPLC (UltraPerformance Liquid Chromatography) was carried out on a Acquity UPLC HSST3 column (1.8 μm, 2.1×100 mm; Waters Acquity) with a flow rate of 0.8ml/min. Two mobile phases (A: 10 mM ammonium acetate in H₂O/acetonitrile95/5; mobile phase B: acetonitrile) were used to run a gradientcondition from 95% A and 5% B to 0% A and 100% B in 2.5 minutes andsubsequently to 5% A and 95% B in 0.5 minutes. An injection volume of 1μl was used. Cone voltage was 30 V for positive ionization mode and 30 Vfor negative ionization mode.

NMR

For a number of compounds, ¹H NMR spectra were recorded on a BrukerDPX-400 spectrometer operating at 400 MHz or on a Bruker DPX-360operating at 360 MHz using CHLOROFORM-d (deuterated chloroform, CDCl₃)or DMSO-d₆ (deuterated DMSO, dimethyl-d6 sulfoxide) as solvent. Chemicalshifts (δ) are reported in parts per million (ppm) relative totetramethylsilane (TMS), which was used as internal standard.

Melting Points

For a number of compounds, melting points (m.p.) were determined with aDSC823e (Mettler-Toledo). Melting points were measured with atemperature gradient of 30° C./minute. Maximum temperature was 400° C.Values are peak values.

Synthesis of Intermediates

All the intermediates needed for the synthesis of targeted compounds offormula (I) are synthesized as described in the following schemes 15 to22.

Step 1: Synthesis of tert-butyl3-(2-nitrophenylamino)azetidine-1-carboxylate 15-d

To a mixture of 2-fluoro-2-nitrobenzene, 15-a (17.278 g, 122.45 mmol, 1eq.), triethylamine (24.782 g, 244.91 mmol, 2.0 eq.) in ethanol (170 mL)at 0° C. tert-butyl 3-aminoazetidine-1-carboxylate (23.2 g, 134.708mmol, 1.1 eq.) was added dropwise. The resulting mixture was refluxedovernight. The mixture was cooled to room temperature and filtrated. Thecake was washed with cooled ethanol and dried under vacuum. 22 g ofintermediate 15-b was obtained (61.5% yield).

Step 2: Synthesis of tert-butyl3-(2-aminophenylamino)azetidine-1-carboxylate 15-c

Intermediate 15-b (21.0 g, 71.595 mmol, 1 eq.) in methanol (70 mL), THF(70 mL) and ethyl acetate (70 mL) was hydrogenated (50 Psi) at 50° C.with Pt/C (2.1 g) as a catalyst for 12 hours. After uptake of H₂ (3eq.), the catalyst was filtered off and the filtrate was evaporated togive intermediate 15-c (18 g, Yield 95.5%).

Step 3: Synthesis of1-cyclopropyl-7-methyl-1H-benzo[d]imidazol-2(3H)-one 15-d

Carbonyldiimidazole (15.517 g, 95.696 mmol, 1.05 eq.) was added to asolution of intermediate 15-c (24.0 g, 91.139 mmol, 1.0 eq.) in CH₃CN(240 mL) at 0° C. The reaction mixture was allowed to warm to 25° C. andstirred for 1 h. The solid was collected by filtration and was washedwith CH₃CN (70 mL) to afford the title intermediate 15-d as a whitepowder (19.35 g, 74%).

Intermediate 16-d was prepared by an analogous reaction protocol asintermediate 15-d using 1,4-difluoro-2-nitrobenzene 16-a as startingmaterial.

Intermediate 17-d was prepared by following an analogous reactionprotocol as described for intermediate 15-d using4-chloro-3-nitropyridine 17-a as starting material.

Intermediate 18-c was prepared by following an analogous reactionprotocol as described for intermediate 15-d using4-chloro-3-nitropyridine 17-a and 1-methyl-cyclopropylamine as startingmaterial.

Intermediate 19-c was prepared by following an analogous reactionprotocol as described for intermediate 15-d using4-chloro-3-nitropyridine 17-a and 2-methyl-propane-2-amine as startingmaterial.

Intermediate 20-c was prepared by following an analogous reactionprotocol as described for intermediate 15-d using4-chloro-3-nitropyridine 17-a and quinolin-6-amine as starting material.

Intermediate 21-c was prepared by following an analogous reactionprotocol as described for intermediate 15-d using4-chloro-3-nitropyridine 17-a and thiazol-2-amine as starting material.

Intermediate 22-c was prepared by following an analogous reactionprotocol as described for intermediate 15-d using4-chloro-3-nitropyridine 17-a and 4-methoxyaniline as starting material.

Step 1: Synthesis of 3-(methylsulfonyl)propan-1-ol 23-b

The alcohol 23-a (200 g, 1900 mmol) was dissolved in CH₂Cl₂ (2000 ml).The mixture was cooled to 0° C. The m-CPBA 85% in water (970 g, 5700mmol) was added portion wise keeping the temperature between 0 to 5° C.After addition, the mixture was allowed to warm to 25° C. and stirredfor 15 h. The mixture was filtered through a celite pad. The filtratewas purified by flash column (Eluent: petroleum ether: ethyl acetate=3:1and then ethyl acetate: methanol=10:1) to yield the intermediate 23-b(75 g, 29%).

Step 2: Synthesis of 1-bromo-3-(methylsulfonyl)propane 23-c

The intermediate 23-b (75 g, 543 mmol) was dissolved in CH₂Cl₂ (750 ml).The mixture was cooled to 0° C. The phosphorus tribromide (53.6 ml, 570mmol) was added drop wise keeping the temperature between 0 to 5° C.After addition, the mixture was allowed to warm to 25° C. and stirredfor 15 h. The mixture was poured into ice-water. The separated organiclayer was washed with brine (2×1500 mL), dried over Na₂SO₄, filtered andevaporated under vacuum to yield the title intermediate 23-c (77 g,71%).

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.25-2.40 (m, 2H) 2.91 (s, 3H)3.1-3.2 (m, 2H) 3.5-3.6 (m, 2H).

Step 1: Synthesis of ethyl5-chloro-1-(3-(methylsulfonyl)propyl)-1H-indole-2-carboxylate 24-b

Ethyl 5-bromo-1H-indole-2-carboxylate 24-a (2.3 g, 8.6 mmol) wasdissolved in DMF (50 mL). The mixture was stirred at room temperature,then sodium hydride 60% suspension in mineral oil (0.52 g, 12.8 mmol)was added. The resulting mixture was stirred at room temperature for 1hour, then 1-bromo-3-(methylsulfonyl)propane 23-c (2.6 g, 12.8 mmol) wasadded. The resulting mixture was stirred at room temperature overnight.The mixture was poured in ice/water solution and extracted with ethylacetate. The organic layer was dried over MgSO₄ and concentrated toyield a brown crude oil. The crude was purified by column chromatographyusing dichloro-methane/methanol to yield the title compound 24-b (3.2 g,96%) as a white solid.

m/z=344 (M+H)⁺.

Step 2: Synthesis of(5-chloro-1-(3-(methylsulfonyl)propyl)-1H-indol-2-yl)methanol 24-c

To a solution of intermediate 24-b (3.2 g, 8.24 mmol) in THF (100 mL)was added at room temperature lithium aluminum hydride (2 M solution inTHF, 5.2 mL, 10.4 mmol). The resulting mixture was stirred at roomtemperature overnight. The reaction mixture was quenched by addition ofethyl acetate and ethanol. The resulting mixture was poured in ice/watersolution then filtered on celite. The aqueous layer was extracted withethyl acetate (3×50 mL). The combined organic extracts were washed withbrine (100 mL), dried over MgSO₄, filtered and concentrated underreduced pressure. The residue was purified by column chromatographyusing dichloromethane/methanol as the eluent. The intermediate 24-c wascollected (2.5 g, 88%) as a white solid. m/z=302 (M+H)⁺.

The following schemes described the synthesis of intermediates neededfor the synthesis of compounds of formula I.

Intermediate 32-c was prepared by following an analogous reactionprotocol as described for intermediate 15-d using4-chloro-3-nitropyridine 17-a and 3,4-dimethoxyaniline as startingmaterial.

Intermediate 33-c was prepared by following an analogous reactionprotocol as described for intermediate 15-d using4-chloro-3-nitropyridine 17-a and 4-methoxy-2-methylaniline as startingmaterial.

Intermediate 34-c was prepared by following an analogous reactionprotocol as described for intermediate 15-d using4-chloro-3-nitropyridine 17-a and pyridin-4-amine as starting material.

Intermediate 35-c was prepared by following an analogous reactionprotocol as described for intermediate 15-d using4-chloro-3-nitropyridine 17-a and pyrimidin-4-amine as startingmaterial.

Intermediate 36-c was prepared by following an analogous reactionprotocol as described for intermediate 15-d using4-chloro-3-nitropyridine 17-a and 3-fluoropyridin-4-amine as startingmaterial.

Intermediate 37-c was prepared by following an analogous reactionprotocol as described for intermediate 16-d using1,4-difluoro-2-nitrobenzene 16-a and thiazol-2-amine as startingmaterial.

Intermediate 38-c was prepared by following an analogous reactionprotocol as described for intermediate 16-d using1,4-difluoro-2-nitrobenzene 16-a and pyridin-4-amine as startingmaterial.

Intermediate 39-c was prepared by following an analogous reactionprotocol as described for intermediate 15-d using4-chloro-3-nitropyridine 17-a and 4-(2-methoxyethoxy)aniline as startingmaterial.

Intermediate 40-c was prepared by following an analogous reactionprotocol as described for intermediate 15-d using4-chloro-3-nitropyridine 17-a and 4-(trifluoromethoxy)aniline asstarting material.

Intermediate 41-c was prepared by following an analogous reactionprotocol as described for intermediate 15-d using4-chloro-3-nitropyridine 17-a, and 4-chloroaniline as starting material.

Intermediate 42-c was prepared by following an analogous reactionprotocol as described for intermediate 15-d using4-chloro-3-nitropyridine 17-a, and 1-methyl-1H-imidazol-2-amine asstarting material.

Intermediate 43-c was prepared by following an analogous reactionprotocol as described for intermediate 15-d using4-chloro-3-nitropyridine 17-a, and oxazol-2-amine as starting material.

Intermediate 44-c was prepared by following an analogous reactionprotocol as described for intermediate 15-d using4-chloro-3-nitropyridine 17-a, and 1-methyl-1H-pyrazol-3-amine asstarting material.

Intermediate 45-c was prepared by following an analogous reactionprotocol as described for intermediate 15-d using4-chloro-3-nitropyridine 17-a, and 3-fluoro-4-methoxyaniline as startingmaterial.

Intermediate 46-c was prepared by following an analogous reactionprotocol as described for intermediate 15-d using4-chloro-3-nitropyridine 17-a, and 2-fluoro-4-methoxyaniline as startingmaterial.

Intermediate 47-c was prepared by following an analogous reactionprotocol as described for intermediate 15-d using4-chloro-3-nitropyridine 17-a, and 4-aminobenzonitrile as startingmaterial.

Step 1: synthesis of4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)benzoic acid 48-a

A solution of4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)benzonitrile 47-c (5g, 21.2 mmol) in 50 mL isopropanol and 50 mL KOH solution (1.5 M inwater) was refluxed during 60 minutes. The solution was poured into anice bath and neutralized to pH=7. The precipitate was filtered off andwashed with water. Dried in the oven to afford a white solid (5 g, 93%).

m/z=256 (M+1)⁺

¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.17 (d, J=5.28 Hz, 1H) 7.71 (d, J=8.58Hz, 2H) 8.12 (d, J=8.58 Hz, 2H) 8.22 (d, J=5.28 Hz, 1H) 8.32 (s, 1H)

Step 2: synthesis of methyl4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)-benzoate 48-c

To a solution of4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)benzoic acid 48-a (3g, 12 mmol) in 100 mL DCM was added thionyl chloride (9 mL, 120 mmol, 10eq.) at room temperature and the solution was refluxed for 16 hours.After concentration to dryness, excess MeOH was added at roomtemperature and stirred for 2 hours. The solution was concentrated invacuo and crystallized with water/MeOH. The solid was filtered off anddried to give 3.1 g (98%) of title intermediate 48-c.

LCMS m/z=270 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.89 (s, 3H) 7.06 (d, J=5.06 Hz, 1H)7.76 (d, J=9.02 Hz, 2H) 8.01 (d, J=4.84 Hz, 1H) 8.10 (d, J=9.02 Hz, 2H)8.18 (s, 1H)

Step 1: synthesis of 2-bromo-6-chloropyridin-3-amine 49-a

Bromine (24.86 g, 155.57 mmol) was added to a solution of6-chloropyridin-3-amine (20.00 g, 155.57 mmol) and sodium acetate (25.52g, 311.14 mmol) in acetic acid (383 ml). The reaction mixture wasstirred at room temperature for 1 hour. Acetic acid was then evaporated.The residue was dissolved in EtOAc, washed with saturated aqueousNa₂CO₃, water and brine. The organic layer was dried over MgSO₄,filtered and evaporated, yielding 32.20 g of the desired product 49-a(99.8%).

m/z=206.96 (M+1)⁺

Step 2: synthesis of 5-chloro-1H-pyrrolo[3,2-b]pyridine-2-carboxylicacid 49-b

2-oxopropanoic acid (36.22 g, 411.31 mmol), palladium(II)acetate (7.74g, 34.15 mmol) and Et₃N (69.11 g, 682.94 mmol) were added to a solutionof 2-bromo-6-chloropyridin-3-amine 49-a (32.20 g, 155.21 mmol) and TPP(35.83 g, 136.59 mmol) in dry DMF (300 ml). The reaction mixture wasstirred at 100° C. overnight. The solvent was then evaporated, water wasadded and the water layer was washed with EtOAc. The water layer wasacidified with conc. HCl. The precipitate was filtered off and dried,yielding 25.21 g of the wanted product 49-b (82.6%).

m/z=197.1 (M+1)⁺.

Step 3: synthesis of methyl5-chloro-1H-pyrrolo[3,2-b]pyridine-2-carboxylate 49-c

5-chloro-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid 49-b (25.20 g,128.18 mmol) was added to a refluxing mixture of sulfuric acid (20 ml)and methanol (400 ml). The mixture was refluxed overnight. The mixturewas then evaporated and a cold NaHCO₃ solution was added until basic pH.The precipitate was filtered off and dried, yielding 16.15 g of thedesired product (59.8%).

m/z=211.17 (M+H)⁺, Cl pattern.

Step 4: synthesis of methyl5-chloro-1-(4,4,4-trifluorobutyl)-1H-pyrrolo[3,2-b]-pyridine-2-carboxylate49-d

To a solution of methyl 5-chloro-1H-pyrrolo[3,2-b]pyridine-2-carboxylate49-c (2.9 g, 12.2 mmol) in DMF (50 mL) were added successively cesiumcarbonate (4 g, 12.2 mmol) and 4-bromo-1,1,1-trifluorobutane (2.3 g,12.2 mmol). The resulting mixture was heated at 60° C. overnight. Thereaction mixture was allowed to cool down to room temperature thenpoured into iced water and the product was extracted 3 times with DCM.The combined organic layers were dried over Na₂SO₄, filtered andevaporated to give the targeted product 49-d as a yellowish solid. Theproduct was used as such in the next step.

m/z=320 (M+1)⁺

Step 5: synthesis of(5-chloro-1-(4,4,4-trifluorobutyl)-1H-pyrrolo[3,2-b]pyridin-2-yl)-methanol49-e

To a solution of methyl5-chloro-1-(4,4,4-trifluorobutyl)-1H-pyrrolo[3,2-b]pyridine-2-carboxylate49-d (3.82 g, 10.8 mmol) in dry THF (100 mL) was added a 1M solution oflithium aluminumhydride (11.96 mL, 11.96 mmol) at −75° C. The coolingbath was then removed and the reaction mixture was kept at roomtemperature for 3 hours. EtOAc was added, followed by a saturated NH₄Clsolution. The mixture was stirred for 30 min. The organic layer wasdried over Na₂SO₄, filtered and evaporated to give a residue, which waspurified by column chromatography to yield the targeted intermediate asa white powder (2.8 g, 98%).

m/z=292 (M+1)⁺

Intermediate 50-c was prepared by following an analogous reactionprotocol as described for intermediate 15-d using4-chloro-3-nitropyridine 17-a, and 4-(methylsulfonyl)aniline as startingmaterial.

Intermediate 51-c was prepared by following an analogous reactionprotocol as described for intermediate 15-d using4-chloro-3-nitropyridine 17-a, and p-toluidine as starting material.

Intermediate 52-c was prepared by following an analogous reactionprotocol as described for intermediate 15-d using4-chloro-3-nitropyridine 17-a, and 2,4-dimethoxyaniline as startingmaterial

Intermediate 53-c was prepared by following an analogous reactionprotocol as described for intermediate 15-d using4-chloro-3-nitropyridine 17-a, and pyrimidin-2-amine as startingmaterial

Synthesis of Compounds Example 1

A detailed description of the synthesis oftert-butyl-3-(3-((5-chloro-1-(3-(methylsulfonyl)propyl)-1H-indol-2-yl)methyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)azetidine-1-carboxylate(P1), a representative example of the invention is given in Scheme 25.

In a 100 mL dry flask, intermediate 17-d (1.9 g, 6.6 mmol),triphenylphosphine (2.08 g, 7.9 mmol, 1.2 eq) and intermediate 24-c (2g, 6.6 mmol) were dissolved in tetrahydrofuran (THF) (60 mL). Thesolution was placed under N₂ atmosphere and diisopropylazodicarboxylate(DIAD) (1.9 mL, 9.9 mmol) was added via syringe. The reaction mixturewas stirred at room temperature under nitrogen overnight. The mixturewas evaporated to dryness and purified by preparative HPLC on an RPVydac Denali C18 column (10 μm, 250 g, 5 cm) using a 0.25% NH₄HCO₃ inwater/CH₃CN solution as the eluent. After evaporation and drying invacuo, 963 mg (25%) of a white solid was obtained.

m/z=574 (M+H)⁺ (LCMS method 1)

MP=195° C.

¹H NMR (400 MHz, DMSO-d6) δ ppm 1.43 (s, 9H) 1.87-2.01 (m, 2H) 2.96 (s,3H) 3.09-3.19 (m, 2H) 4.22-4.44 (m, 6H) 5.21-5.31 (m, 1H) 5.35 (s, 2H)6.55 (s, 1H) 7.17 (dd, J=8.80, 1.98 Hz, 1H) 7.31 (d, J=5.28 Hz, 1H)7.52-7.59 (m, 2H) 8.29 (d, J=5.28 Hz, 1H) 8.48 (s, 1H)

Example 2 Synthesis of tert-butyl3-(3-((5-chloro-1-(3-(methylsulfonyl)propyl)-1H-indol-2-yl)methyl)-5-fluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)azetidine-1-carboxylate(P2)

Compound P2 was prepared by following an analogous reaction protocol asdescribed for compound P1 using intermediate 24-c and tert-butyl3-(5-fluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)azetidine-1-carboxylate5-d as starting material.

m/z=591 (M+H)⁺ (LCMS Method 1)

MP=185° C.

¹H NMR (400 MHz, DMSO-d6) δ ppm 1.43 (s, 9H) 1.90-2.01 (m, 2H) 2.97 (s,3H) 3.10-3.18 (m, 2H) 4.23-4.45 (m, 6H) 5.22-5.28 (m, 1H) 5.29 (s, 2H)6.46 (s, 1H) 6.94-7.02 (m, 1H) 7.16 (dd, J=8.69, 2.09 Hz, 1H) 7.22-7.29(m, 2H) 7.51-7.58 (m, 2H)

Example 3 Synthesis of1-(azetidin-3-yl)-3-((5-chloro-1-(3-(methylsulfonyl)propyl)-1H-indol-2-yl)methyl)-5-fluoro-1H-benzo[d]imidazol-2(3H)-one(P3)

To a solution of compound P2 (800 mg, 1.353 mmol) in dichloromethane (10mL) was added trifluoroacetic acid (1.036 ml, 13.534 mmol) at roomtemperature. The reaction mixture was stirred for 16 h. The reactionmixture was quenched with some iced water and the pH was basified with asaturated aqueous NaHCO₃ solution. Then dichloro-methane was evaporatedand the pink solid in water was stirred at room temperature for 12 hoursthen was filtered off. The solid was washed with water and isopropylether to give 536 mg of the desired compound (P3) as a beige solid(yield=78%). P3 was obtained as a trifluoroacetate salt form (0.0.17CF₃COOH).

m/z=491 (M+H)⁺ (LCMS method 1)

¹H NMR (400 MHz, DMSO-d6) δ ppm 1.84-2.06 (m, 2H) 2.96 (s, 3H) 3.08-3.17(m, 2H) 3.81-3.94 (m, 2H) 3.98-4.06 (m, 2H) 4.40 (t, J=7.59 Hz, 2H)5.18-5.27 (m, 1H) 5.28 (s, 2H) 6.42 (s, 1H) 6.91-7.00 (m, 1H) 7.15 (dd,J=8.69, 2.09 Hz, 1H) 7.23 (dd, J=9.24, 2.42 Hz, 1H) 7.53 (d, J=8.80 Hz,1H) 7.56 (d, J=1.98 Hz, 1H) 7.75 (dd, J=8.69, 4.51 Hz, 1H)

Example 4 Synthesis of1-(azetidin-3-yl)-3-((5-chloro-1-(3-(methylsulfonyl)propyl)-1H-indol-2-yl)methyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one(P4)

Compound P4 was prepared by an analogous reaction protocol as describedfor compound P3. P4 was obtained as a trifluoroacetate salt (CF₃COOH).

m/z=474 (M+H)⁺ (LCMS Method 1)

¹H NMR (400 MHz, DMSO-d6) δ ppm 1.92-2.05 (m, 2H) 2.97 (s, 3H) 3.09-3.20(m, 2H) 4.19-4.31 (m, 2H) 4.40 (t, J=7.70 Hz, 2H) 4.55-4.66 (m, 2H)5.32-5.46 (m, 3H) 6.56 (s, 1H) 7.17 (dd, J=9.02, 2.20 Hz, 1H) 7.52 (d,J=5.28 Hz, 1H) 7.54-7.58 (m, 2H) 8.30 (d, J=5.28 Hz, 1H) 8.49 (s, 1H)8.73 (br. s, 1H)

Example 5 Synthesis of3-((5-chloro-1-(3-(methylsulfonyl)propyl)-1H-indol-2-yl)methyl)-1-(1-(methylsulfonyl)azetidin-3-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one(P5)

To a solution of P4 (350 mg, 0.6 mmol) in dichloromethane (20 mL)triethyl amine (0.248 mL, 1.8 mmol) was added. The mixture was stirredat RT then methanesulfonyl chloride (0.0485 mL, 0.625 mmol) was added atroom temperature. The resulting mixture was stirred at room temperaturefor 24 hours. A thick white precipitate was seen in the flask. Thereaction mixture was washed with saturated NaHCO₃. The organic layer wasseparated, dried on MgSO₄ and concentrated. The resulting solid wasrefluxed in methanol. After cooling down to room temperature theprecipitate was filtered off and dried in vacuum for 2 hours to givecompound P5 (110 mg, 32%) as an off white solid.

m/z=552 (M+H)⁺ (LCMS method 1)

MP=240° C.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.87-2.02 (m, 2H), 2.97 (s, 3H),3.09-3.20 (m, 5H), 4.29 (t, J=8.80 Hz, 2H), 4.39 (t, J=7.59 Hz, 2H),4.50 (dd, J=8.91, 6.49 Hz, 2H), 5.30-5.40 (m, 3H), 6.56 (s, 1H), 7.17(dd, J=8.69, 2.09 Hz, 1H), 7.49-7.60 (m, 3H), 8.31 (d, J=5.28 Hz, 1H),8.48 (s, 1H)

Example 6 Synthesis of1-(1-acetylazetidin-3-yl)-3-((5-chloro-1-(3-(methylsulfonyl)propyl)-1H-indol-2-yl)methyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one(P6)

Compound P6 was prepared by an analogous reaction protocol as describedfor compound P5 using P4 and acetyl chloride as starting material.

m/z=516 (M+H)⁺ (LCMS method 1)

MP=252° C.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.86 (s, 3H), 1.94 (ddd, J=15.24, 8.03,7.76 Hz, 2H), 2.97 (s, 3H), 3.11-3.19 (m, 2H), 4.22-4.35 (m, 2H), 4.39(t, J=7.70 Hz, 2H), 4.50-4.58 (m, 1H), 4.59-4.66 (m, 1H), 5.30 (tt,J=8.39, 5.69 Hz, 1H), 5.35 (s, 2H), 6.56 (s, 1H), 7.17 (dd, J=8.80, 1.98Hz, 1H), 7.33 (d, J=5.28 Hz, 1H), 7.52-7.59 (m, 2H), 8.29 (d, J=5.28 Hz,1H), 8.48 (s, 1H)

Example 7 Synthesis of3-((5-chloro-1-(3-(methylsulfonyl)propyl)-1H-indol-2-yl)methyl)-1-(1-methylcyclopropyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one(P7)

Compound P7 was prepared by an analogous reaction protocol as describedfor compound P1 using intermediate 24-c and1-(1-methylcyclopropyl)-1H-imidazo-[4,5-c]pyridin-2(3H)-one 18-c asstarting material.

m/z=473 (M+H)⁺ (LCMS method 1)

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.97-1.02 (m, 2H), 1.06-1.12 (m, 2H),1.43 (s, 3H), 1.92-2.04 (m, 2H), 2.97 (s, 3H), 3.10-3.18 (m, 2H), 4.39(t, J=7.5 Hz, 2H), 5.31 (s, 2H), 6.49 (s, 1H), 7.16 (dd, J=8.7, 2.1 Hz,1H), 7.31 (dd, J=5.3, 0.4 Hz, 1H), 7.54 (d, J=8.8 Hz, 1H), 7.57 (d,J=2.0 Hz, 1H), 8.26 (d, J=5.1 Hz, 1H), 8.40 (s, 1H)

Example 8 Synthesis of1-tert-butyl-3-((5-chloro-1-(3-(methylsulfonyl)propyl)-1H-indol-2-yl)methyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one(P8)

Compound P8 was prepared by an analogous reaction protocol as describedfor compound P1 using fragment A-c and1-tert-butyl-1H-imidazo[4,5-c]pyridin-2(3H)-one 19-c as startingmaterial.

m/z=475 (M+H)⁺ (LCMS method 2)

MP=226° C.

1H NMR (400 MHz, DMSO-d6) δ ppm 1.74 (s, 9H) 1.93-2.06 (m, 2H) 2.97 (s,3H) 3.10-3.20 (m, 2H) 4.40 (t, J=7.48 Hz, 2H) 5.31 (s, 2H) 6.42 (s, 1H)7.16 (dd, J=8.69, 2.09 Hz, 1H) 7.47-7.61 (m, 3H) 8.14 (d, J=5.72 Hz, 1H)8.41 (s, 1H)

Example 9 Synthesis of3-((5-chloro-1-(4,4,4-trifluorobutyl)-1H-imidazo[4,5-b]pyridin-2-yl)-methyl)-1-(1-methylcyclopropyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one(P9) scheme 26

Step 1: Synthesis of6-chloro-N³-(4,4,4-trifluorobutyl)-pyridine-2,3-diamine 26-b

The intermediate 26-a (5 g, 34.82 mmol) was dissolved in dichloromethane(200 mL), acetic acid (20 drops) and 4,4,4-trifluorobutanal (4.38 g,34.8 mmol) were added. The resulting mixture was stirred for 30 minutesand then sodium triacetoxyhydroborate (22.14 g, 104.5 mmol) was added.The reaction mixture was stirred at room temperature overnight and asolution of 50% Na₂CO₃ was added dropwise until gas evolution stopped.The organic layer was separated, dried on MgSO₄, filtrated andevaporated to dryness. The residue was purified by column chromatographyusing heptane/EtOAc 7/3 to pure EtOAc. Intermediate 26-b was recoveredas a white solid and dried in vacuo overnight (6.16 g, 70%). m/z=254(M+H)⁺.

Step 2: Synthesis of(5-chloro-1-(4,4,4-trifluorobutyl)-1H-imidazo[4,5-b]pyridin-2-yl)-methanol26-c

A mixture of intermediate 26-b (5.68 g, 22.46 mmol) and 2-hydroxyaceticacid (4.27 g, 56.2 mmol) was stirred at 150° C. for 4 hours. The mixturewas allowed to cool down to room temperature and treated carefully with3N hydrochloric acid. The resulting mixture was made basic with aqueousammonia and extracted with CH₂Cl₂ (300 mL). The organic layer was driedover MgSO₄ and evaporated to dryness. The residue was purified by columnchromatography on silica using CH₂Cl₂ to EtOAc. The intermediate 26-cwas isolated as brown solid (4.27 g, 65%).

m/z=294 (M+H)⁺.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.00 (s, 2H), 1.12-1.23 (m, 2H),1.83-1.99 (m, 2H), 2.12-2.31 (m, 2H), 2.91 (spt, J=3.50 Hz, 1H),4.38-4.54 (m, 2H), 5.38 (s, 2H), 7.13 (dd, J=5.27, 0.50 Hz, 1H), 7.27(d, J=8.28 Hz, 1H), 7.61 (d, J=8.53 Hz, 1H), 8.36 (d, J=5.27 Hz, 1H),8.77 (s, 1H)

Synthesis of3-((5-chloro-1-(4,4,4-trifluorobutyl)-1H-imidazo[4,5-b]pyridin-2-yl)methyl)-1-(1-methylcyclopropyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one(P9)

Compound P9 was prepared by an analogous reaction protocol as describedfor compound P1 using intermediate 26-c and1-(1-methylcyclopropyl)-1H-imidazo-[4,5-c]pyridin-2(3H)-one 18-c asstarting material.

m/z=465 (M+H)⁺ (LCMS method 2)

1H NMR (400 MHz, DMSO-d6) δ ppm 0.94-1.09 (m, 4H) 1.42 (s, 3H) 1.89-2.01(m, 2H) 2.30-2.45 (m, 2H) 4.48 (t, J=7.59 Hz, 2H) 5.47 (s, 2H) 7.33 (d,J=5.28 Hz, 1H) 7.38 (d, J=8.36 Hz, 1H) 8.22 (d, J=8.36 Hz, 1H) 8.28 (d,J=5.28 Hz, 1H) 8.45 (s, 1H)

Example 10 Synthesis of3-((5-chloro-1-(4-fluorobutyl)-1H-imidazo[4,5-b]pyridin-2-yl)methyl)-1-(thiazol-2-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one(P10)

Intermediate 27-a was prepared by an analogous reaction protocol asdescribed for intermediate 26-c using intermediate 26-a and4-fluorobutanal as starting material. Compound P10 was prepared by ananalogous reaction protocol as described for compound P1 usingintermediate 27-a and1-(thiazol-6-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one 21-c as startingmaterial.

MP=238° C.

m/z=458 (M+H)⁺

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.71-1.93 (m, 2H), 4.39 (t, J=5.6Hz, 1H), 4.42-4.48 (m, 1H), 4.51 (t, J=5.4 Hz, 1H), 5.53 (s, 1H), 7.23(d, J=3.5 Hz, 1H), 7.27 (d, J=8.4 Hz, 1H), 7.65 (d, J=8.4 Hz, 1H), 7.70(d, J=3.5 Hz, 1H), 8.41 (dd, J=5.4, 0.6 Hz, 1H), 8.53 (d, J=5.3 Hz, 1H),8.91 (s, 1H)

Example 11 Synthesis of3-((5-chloro-1-(4-fluorobutyl)-1H-indol-2-yl)methyl)-1-(thiazol-2-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one(P11)

Intermediate 28-a was prepared by an analogous reaction protocol asdescribed for intermediate 24-c using intermediate 24-a and1-bromo-4-fluorobutane as starting material.

Compound P11 was prepared by an analogous reaction protocol as describedfor compound P1 using intermediate 28-a and1-(thiazol-6-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one 21-c as startingmaterial.

MP=240° C.

m/z=456 (M+H)⁺

¹H NMR (360 MHz, DMSO-d₆) δ ppm 1.51-1.64 (m, 3H), 1.69 (m, J=5.5 Hz,1H), 4.24-4.36 (m, 3H), 4.41 (t, J=6.0 Hz, 1H), 5.48 (s, 2H), 6.64 (s,1H), 7.15 (dd, J=8.8, 2.2 Hz, 1H), 7.52 (d, J=8.8 Hz, 1H), 7.57 (d,J=2.2 Hz, 1H), 7.63 (d, J=3.7 Hz, 1H), 7.79 (d, J=3.3 Hz, 1H), 8.33 (d,J=5.1 Hz, 1H), 8.45 (d, J=5.5 Hz, 1H), 8.63 (s, 1H)

Example 12 Synthesis of3-((5-chloro-1-(3(methylsulfonyl)propyl)-1H-indol-2-yl)methyl)-5-fluoro-1-(1-(2-hydroxy-2-methylpropyl)azetidin-3-yl)-1H-benzo[d]imidazol-2(3H)-one(P12)

Compound P3 (150 mg, 0.3 mmol) was dissolved in ethanol (5 mL),triethylamine (133 μL, 0.88 mmol) and 2,2-dimethyloxerane (40 μL, 0.45mmol) were added. The resulting mixture was stirred at 60° C. overnight.The reaction mixture was allowed to cool down to room temperature thanevaporated to dryness. The residue was purified by column chromatographyusing CH₂Cl₂/MeOH:9/1. Compound P12 was recovered as a white solid anddried in vacuo overnight (130 mg, 78%).

m/z=463 (M+H)⁺

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.19 (s, 6H), 2.11 (quin, J=7.59Hz, 2H), 2.63 (br. s, 3H), 2.85 (s, 3H), 2.96-3.03 (m, 2H), 3.87-3.96(m, 4H), 4.37-4.44 (m, 2H), 5.08 (qd, J=7.08, 6.93 Hz, 1H), 5.18 (s,2H), 6.56 (s, 1H), 6.83 (td, J=9.13, 2.42 Hz, 1H), 6.92 (dd, J=8.36,2.42 Hz, 1H), 7.14-7.19 (m, 1H), 7.20-7.25 (m, 1H), 7.51 (dd, J=8.58,4.40 Hz, 1H), 7.55 (d, J=1.54 Hz, 1H)

Example 13 Synthesis of3-((5-chloro-1-isopentyl-1H-imidazo[4,5-b]pyridin-2-yl)methyl)-1-(quinolin-6-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one(P13)

Intermediate 30-a was prepared by an analogous reaction protocol asdescribed for intermediate 26-c using intermediate 26-a and3-methylbutanal as starting material. Compound P13 was prepared by ananalogous reaction protocol as described for compound P1 usingintermediate 30-a and1-(quinolin-6-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one 20-c as startingmaterial.

m/z=498 (M+H)⁺

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.00 (d, J=6.38 Hz, 6H), 1.58-1.66(m, 2H), 1.67-1.79 (m, 1H), 4.37-4.48 (m, 2H), 5.52 (s, 2H), 7.09 (dd,J=5.50, 0.66 Hz, 1H), 7.23-7.28 (m, 1H), 7.51 (dd, J=8.36, 4.18 Hz, 1H),7.64 (d, J=8.36 Hz, 1H), 7.84 (dd, J=9.02, 2.42 Hz, 1H), 8.01 (d, J=2.42Hz, 1H), 8.23 (dd, J=8.47, 0.99 Hz, 1H), 8.31 (d, J=8.80 Hz, 1H), 8.38(d, J=5.28 Hz, 1H), 8.89 (s, 1H), 9.02 (dd, J=4.29, 1.65 Hz, 1H)

Example 14 Synthesis of4-(5-chloro-2-((1-(4-methoxyphenyl)-2-oxo-1H-imidazo[4,5-c]pyridin-3(2H)-yl)methyl)-1H-indol-1-yl)butanenitrile(P14)

Step 1: synthesis of ethyl5-chloro-1-(3-cyanopropyl)-1H-indole-2-carboxylate 31-a

Ethyl-5-chloroindol-2-carboxylate 24-a (33.55 g, 150 mmol) was dissolvedin acetonitrile (600 mL) and stirred at room temperature. Thencesiumcarbonate (73.31 g, 225 mmol) was added and stirring was continuedfor 30 minutes. 4-Bromobutyronitrile (18.83 mL, 180 mmol) was added insmall portions over a period of one hour and stirring was done overnightat ambient temperature. The reaction mixture was filtered and thefiltrate was evaporated to dryness. The residue was dissolved indichloro-methane and washed with water. The organic layer was dried overMgSO4, filtered and evaporated. The residue 43.5 g was used as such inthe next step 99% yield.

m/z=290 (M+H)⁺

Step 2: Synthesis of 5-Chloro-1-(3-cyanopropyl)-1H-indole-2-carboxylicacid 31-b

Ethyl 5-chloro-1-(3-cyanopropyl)indol-2-carboxylate 31-a (43.61 g,149.97 mmol) was dissolved in 1,4-dioxane (850 mL) and stirred at roomtemperature. Then a solution of lithiumhydroxide (10.78 g, 450 mmol) indistilled water (150 mL) was added the stirring was continued overnightat ambient temperature. The reaction mixture was evaporated to dryness.The residue was dissolved in 500 mL water and neutralised with aqueoussolution of hydrochloric acid 1 N (450 mL). The white precipitate wasfiltered off and dried in vacuo to yield 39.8 g of the intermediate 31-b100%.

m/z=262 (M+H)⁺

Step 3: Synthesis of4-(5-chloro-2-(hydroxymethyl)-1H-indol-1-yl)butanenitrile 31-c

5-chloro-1-(3-cyanopropyl)indol-2-carboxylic acid 31-b (39.4 g, 149.98mmol) and Hunigs base (51.69 mL, 300 mmol) were dissolved intetrahydrofuran (550 mL) and stirred at −10° C. under a nitrogenatmosphere. Then a solution of isoButylchloroformate in tetrahydrofuran(50 ml) was added dropwise the stirring was continued for one hour at−10° C. and one hour at ambient temperature. Then sodiumborohydride(17.02 g, 450 mmol) was added portionwise at −10° C. and stirred for onehour, afterwards distilled water (200 mL) was added cautiously to thereaction mixture and stirring was continued for another hour at roomtemperature under a nitrogen atmosphere. The mixture was neutralisedwith 10% citric acid in water and then extracted with ethyl acetate. Theorganic layer was dried over MgSO4, filtered and evaporated. The residuewas purified over silica with Heptane/dichloromethane/methanol50/50/0->0/100/0->0/99/1 as gradient. The corresponding fractions wereevaporated to yield the intermediate 31-c 23.9 g as a white powder 64%.

m/z=248 (M+H)⁺

Step 4: Synthesis of4-(5-chloro-2-((1-(4-methoxyphenyl)-2-oxo-1H-imidazo[4,5-c]pyridin-3(2H)-yl)methyl)-1H-indol-1-yl)butanenitrile(P14)

To a suspention of intermediate 31-c (3 g, 12.02 mmol), intermediate22-c (2.9 g, 12.02 mmol) and triphenylphosphine (3.78 g, 14.43 mmol) indry THF (90 mL) diisopropylazodicarboxylate (DIAD) (3.509 ml, 18.03mmol) was added at room temperature dropwise. The resulting mixture wasstirred overnight. The solvent was evaporated and the residue wastriturated in ether. After stirring for 1 hour, the solid was filteredoff and then the beige powder was crystallized in MeOH. The formedcrystals were filtered off and washed with some MeOH and ether to getthe title product P14 as a white powder (2.2 g, 40%).

m/z=472 (M+H)⁺

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.95 (quin, J=7.59 Hz, 2H) 2.54 (t,J=7.50 Hz, 2H) 3.84 (s, 3H) 4.35 (t, J=7.70 Hz, 2H) 5.42 (s, 2H) 6.55(s, 1H) 7.02 (d, J=5.28 Hz, 1H) 7.11-7.19 (m, 3H) 7.47-7.52 (m, 2H) 7.54(d, J=8.80 Hz, 1H) 7.57 (d, J=1.98 Hz, 1H) 8.23 (d, J=5.28 Hz, 1H) 8.51(s, 1H)

Example 15 Synthesis of4-(5-chloro-2-((1-(3-fluoro-4-methoxyphenyl)-2-oxo-1H-imidazo[4,5-c]pyridin-3(2H)-yl)methyl)-1H-indol-1-yl)butanenitrile(P15)

Compound P15 was prepared by an analogous reaction protocol as describedfor compound P1 using intermediate 31-c and1-(3-fluoro-4-methoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one 45-c asstarting material.

m/z=490 (M+1)⁺

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.01 (qd, J=7.37, 7.15 Hz, 2H),2.36 (t, J=7.15 Hz, 2H), 3.97 (s, 3H), 4.34-4.45 (m, 2H), 5.31 (s, 2H),6.69 (s, 1H), 6.99 (dd, J=5.28, 0.66 Hz, 1H), 7.09-7.16 (m, 1H),7.16-7.30 (m, 4H), 7.56 (d, J=1.54 Hz, 1H), 8.32 (d, J=5.28 Hz, 1H),8.51 (s, 1H)

Example 16 Synthesis of3-((5-chloro-1-isopentyl-1H-imidazo[4,5-b]pyridin-2-yl)methyl)-1-(4-methoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one(P16)

Compound P16 was prepared by an analogous reaction protocol as describedfor compound P1 using intermediate 30-a and1-(4-methoxyphenyl)-1H-imidazo-[4,5-c]pyridin-2(3H)-one 22-c as startingmaterial.

m/z=477 (M+1)⁺

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.98 (d, J=6.60 Hz, 6H), 1.52-1.63(m, 2H), 1.68 (s, 1H), 3.88 (s, 3H), 4.34-4.46 (m, 2H), 5.48 (s, 2H),6.93 (d, J=5.28 Hz, 1H), 7.02-7.09 (m, 2H), 7.24 (d, J=8.58 Hz, 1H),7.33-7.41 (m, 2H), 7.62 (d, J=8.36 Hz, 1H), 8.32 (d, J=5.50 Hz, 1H),8.82 (s, 1H)

Example 17 Synthesis of3-((5-chloro-1-(4,4,4-trifluorobutyl)-1H-pyrrolo[3,2-b]pyridin-2-yl)-methyl)-1-(4-methoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one(P17)

Compound P17 was prepared by an analogous reaction protocol as describedfor compound P1 using intermediate 49-e and1-(4-methoxyphenyl)-1H-imidazo[4,5-c]-pyridin-2(3H)-one 22-c as startingmaterial.

m/z=516 (M+1)⁺

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.80-1.92 (m, 2H), 2.04-2.21 (m,2H), 3.88 (s, 3H), 4.32-4.42 (m, 2H), 5.36 (s, 2H), 6.90 (s, 1H), 6.95(d, J=5.28 Hz, 1H), 7.05-7.11 (m, 2H), 7.16 (d, J=8.58 Hz, 1H),7.34-7.41 (m, 2H), 7.54 (d, J=8.58 Hz, 1H), 8.31 (d, J=5.06 Hz, 1H),8.49 (s, 1H)

Example 18 Synthesis of3-((5-chloro-1-isopentyl-1H-imidazo[4,5-b]pyridin-2-yl)methyl)-1-(1-methylcyclopropyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one(P18)

Compound P18 was prepared by an analogous reaction protocol as describedfor compound P1 using intermediate 30-a and1-(1-methylcyclopropyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one 18-c asstarting material.

m/z=425 (M+1)⁺

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.99 (d, J=6.60 Hz, 6H), 1.02-1.07(m, 2H), 1.11-1.19 (m, 2H), 1.50 (s, 3H), 1.52-1.60 (m, 2H), 1.63-1.78(m, 1H), 4.30-4.42 (m, 2H), 5.37 (s, 2H), 7.13 (d, J=5.06 Hz, 1H), 7.20(d, J=8.36 Hz, 1H), 7.60 (d, J=8.36 Hz, 1H), 8.34 (d, J=3.74 Hz, 1H),8.71 (br. s., 1H)

Example 19 Synthesis of4-(5-chloro-2-((1-(3,4-dimethoxyphenyl)-2-oxo-1H-imidazo[4,5-c]pyridin-3(2H)-yl)methyl)-1H-indol-1-yl)butanenitrile(P19)

Compound P19 was prepared by an analogous reaction protocol as describedfor compound P1 using intermediate 31-c and1-(3,4-dimethoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one 32-c asstarting material.

m/z=502 (M+1)⁺

MP=176.51° C.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.94 (quin, J=7.48 Hz, 2H) 2.52-2.58 (m,2H) 3.79 (s, 3H) 3.84 (s, 3H) 4.32-4.40 (m, 2H) 5.42 (s, 2H) 6.56 (s,1H) 7.05-7.20 (m, 5H) 7.55 (d, J=8.80 Hz, 1H) 7.57 (d, J=1.98 Hz, 1H)8.23 (d, J=5.28 Hz, 1H) 8.51 (s, 1H)

Example 20 Synthesis of4-(5-chloro-2-((1-(4-methoxy-2-methylphenyl)-2-oxo-1H-imidazo[4,5-c]pyridin-3(2H)-yl)methyl)-1H-indol-1-yl)butanenitrile(P20)

Compound P20 was prepared by an analogous reaction protocol as describedfor compound P1 using intermediate 31-c and1-(4-methoxy-2-methylphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one 33-c asstarting material.

m/z=486 (M+1)⁺

MP=172.59° C.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.89-2.05 (m, 2H) 2.07 (s, 3H) 2.52-2.60(m, 2H) 3.83 (s, 3H) 4.26-4.42 (m, 2H) 5.43 (s, 2H) 6.50 (s, 1H) 6.76(d, J=5.06 Hz, 1H) 6.96 (dd, J=8.69, 2.75 Hz, 1H) 7.06 (d, J=2.64 Hz,1H) 7.17 (dd, J=8.69, 2.09 Hz, 1H) 7.34 (d, J=8.58 Hz, 1H) 7.55 (d,J=8.80 Hz, 1H) 7.58 (d, J=1.98 Hz, 1H) 8.21 (d, J=5.28 Hz, 1H) 8.51 (s,1H)

Example 21 Synthesis of4-(5-chloro-2-((2-oxo-1-(pyrimidin-2-yl)-1H-imidazo[4,5-c]pyridin-3(2H)-yl)methyl)-1H-indol-1-yl)butanenitrile(P21)

Compound P21 was prepared by an analogous reaction protocol as describedfor compound P1 using intermediate 31-c and1-(pyrimidin-2-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one 53-c as startingmaterial.

m/z=445 (M+1)⁺

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.91 (quin, J=7.65 Hz, 2H) 2.54-2.63 (m,2H) 4.28-4.43 (m, 2H) 5.45 (s, 2H) 6.52 (s, 1H) 7.16 (dd, J=8.69, 2.09Hz, 1H) 7.54 (d, J=8.80 Hz, 1H) 7.57 (d, J=2.20 Hz, 1H) 7.61 (t, J=4.84Hz, 1H) 7.77 (dd, J=5.39, 0.77 Hz, 1H) 8.33 (d, J=5.28 Hz, 1H) 8.58 (s,1H) 9.02 (d, J=4.84 Hz, 2H)

Example 22 Synthesis of3-((5-chloro-1-isopentyl-1H-imidazo[4,5-b]pyridin-2-yl)methyl)-1-(thiazol-2-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one(P22)

Compound P22 was prepared by an analogous reaction protocol as describedfor compound P1 using intermediate 30-a and1-(thiazol-2-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one 21-c as startingmaterial.

m/z=454 (M+1)⁺

MP=231.23° C. and 238.22° C.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.95 (d, J=6.38 Hz, 6H) 1.56-1.77 (m,3H) 4.35-4.50 (m, 2H) 5.67 (s, 2H) 7.37 (d, J=8.36 Hz, 1H) 7.63 (d,J=3.52 Hz, 1H) 7.81 (d, J=3.52 Hz, 1H) 8.16 (d, J=8.36 Hz, 1H) 8.35 (d,J=5.28 Hz, 1H) 8.49 (d, J=5.28 Hz, 1H) 8.68 (s, 1H)

Example 23 Synthesis of3-((5-chloro-1-isopentyl-1H-imidazo[4,5-b]pyridin-2-yl)methyl)-1-(pyridin-4-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one(P23)

Compound P23 was prepared by an analogous reaction protocol as describedfor compound P1 using intermediate 30-a and1-(pyridin-4-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one 34-c as startingmaterial.

m/z=448 (M+1)⁺

MP=210

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.95 (d, J=6.16 Hz, 6H) 1.57-1.75 (m,3H) 4.34-4.49 (m, 2H) 5.60 (s, 2H) 7.37 (d, J=8.58 Hz, 1H) 7.44 (d,J=5.28 Hz, 1H) 7.70-7.80 (m, 2H) 8.16 (d, J=8.58 Hz, 1H) 8.34 (d, J=5.50Hz, 1H) 8.62 (s, 1H) 8.75-8.85 (m, 2H)

Example 24 Synthesis of4-(5-chloro-2-((2-oxo-1-(pyrimidin-4-yl)-1H-imidazo[4,5-c]pyridin-3(2H)-yl)methyl)-1H-indol-1-yl)butanenitrile(P24)

Compound P24 was prepared by an analogous reaction protocol as describedfor compound P1 using intermediate 31-c and1-(pyrimidin-4-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one 35-c as startingmaterial.

m/z=444 (M+1)⁺

MP=229.17° C.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.98 (quin, J=7.32 Hz, 2H) 2.58 (t,J=7.37 Hz, 2H) 4.36 (t, J=7.59 Hz, 2H) 5.46 (s, 2H) 6.51 (s, 1H) 7.16(dd, J=8.80, 1.76 Hz, 1H) 7.48-7.60 (m, 2H) 8.34 (d, J=5.28 Hz, 1H)8.38-8.47 (m, 2H) 8.60 (s, 1H) 8.97 (d, J=5.94 Hz, 1H) 9.24 (s, 1H)

Example 25 Synthesis of3-((5-chloro-1-isopentyl-1H-imidazo[4,5-b]pyridin-2-yl)methyl)-5-fluoro-1-(thiazol-2-yl)-1H-benzo[d]imidazol-2(3H)-one(P25)

Compound P25 was prepared by an analogous reaction protocol as describedfor compound P1 using intermediate 30-a and5-fluoro-1-(thiazol-2-yl)-1H-benzo[d]imidazol-2(3H)-one 37-c as startingmaterial.

m/z=471 (M+1)⁺

MP=264.42° C.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.94 (d, J=6.38 Hz, 6H) 1.54-1.74 (m,3H) 4.34-4.47 (m, 2H) 5.61 (s, 2H) 7.07-7.18 (m, 1H) 7.36 (d, J=8.36 Hz,1H) 7.42 (dd, J=8.91, 2.53 Hz, 1H) 7.57 (d, J=3.52 Hz, 1H) 7.75 (d,J=3.52 Hz, 1H) 8.16 (d, J=8.36 Hz, 1H) 8.46 (dd, J=8.80, 4.84 Hz, 1H)

Example 26 Synthesis of3-((5-chloro-1-isopentyl-1H-imidazo[4,5-b]pyridin-2-yl)methyl)-1-(3-fluoropyridin-4-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one(P26)

Compound P26 was prepared by an analogous reaction protocol as describedfor compound P1 using intermediate 30-a and1-(3-fluoropyridin-4-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one 36-c asstarting material.

m/z=466 (M+1)⁺

MP=123.79° C.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.94 (d, J=6.16 Hz, 6H) 1.57-1.74 (m,3H) 4.35-4.48 (m, 2H) 5.62 (s, 2H) 7.20 (dd, J=5.06, 2.20 Hz, 1H) 7.37(d, J=8.36 Hz, 1H) 7.83 (t, J=5.83 Hz, 1H) 8.16 (d, J=8.36 Hz, 1H) 8.33(d, J=5.28 Hz, 1H) 8.62 (s, 1H) 8.68 (d, J=5.06 Hz, 1H) 8.93 (d, J=1.98Hz, 1H)

Example 27 Synthesis of4-(5-chloro-2-((6-fluoro-2-oxo-3-(thiazol-2-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)-1H-indol-1-yl)butanenitrile(P27)

Compound P27 was prepared by an analogous reaction protocol as describedfor compound P1 using intermediate 31-c and5-fluoro-1-(thiazol-2-yl)-1H-benzo[d]imidazol-2(3H)-one 37-c as startingmaterial.

m/z=466 (M+1)⁺

MP=238.29° C.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.90-2.04 (m, 2H) 2.58 (t, J=7.37 Hz,2H) 4.31-4.43 (m, 2H) 5.44 (s, 2H) 6.40 (s, 1H) 7.07-7.14 (m, 1H) 7.16(dd, J=8.80, 1.98 Hz, 1H) 7.41 (dd, J=8.91, 2.53 Hz, 1H) 7.49-7.60 (m,3H) 7.75 (d, J=3.52 Hz, 1H) 8.46 (dd, J=8.91, 4.95 Hz, 1H)

Example 28 Synthesis of4-(5-chloro-2-((1-(4-(2-methoxyethoxy)phenyl)-2-oxo-1H-imidazo[4,5-c]pyridin-3(2H)-yl)methyl)-1H-indol-1-yl)butanenitrile(P28)

Compound P28 was prepared by an analogous reaction protocol as describedfor compound P1 using intermediate 31-c and1-(4-(2-methoxyethoxy)phenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one 39-c asstarting material.

m/z=516 (M+1)⁺

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.98 (quin, J=7.5 Hz, 2H), 2.51-2.58 (m,2H), 3.34 (s, 3H), 3.65-3.75 (m, 2H), 4.14-4.24 (m, 2H), 4.36 (t, J=7.7Hz, 2H), 5.40 (s, 2H), 6.53 (s, 1H), 6.99 (d, J=5.2 Hz, 1H), 7.09-7.18(m, 3H), 7.42-7.57 (m, 4H), 8.22 (d, J=5.2 Hz, 1H), 8.46 (s, 1H)

Example 29 Synthesis of4-(5-chloro-2-((2-oxo-1-(4-(trifluoromethoxy)phenyl)-1H-imidazo[4,5-c]pyridin-3(2H)-yl)methyl)-1H-indol-1-yl)butanenitrile(P29)

Compound P29 was prepared by an analogous reaction protocol as describedfor compound P1 using intermediate 31-c and1-(4-(trifluoromethoxy)phenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one 40-cas starting material.

m/z=526 (M+1)⁺

¹H NMR (360 MHz, DMSO-d₆) δ ppm 1.97 (quin, J=7.5 Hz, 2H), 2.56 (t,J=7.5 Hz, 2H), 4.36 (t, J=7.5 Hz, 2H), 5.44 (s, 2H), 6.56 (s, 1H),7.09-7.25 (m, 2H), 7.50-7.69 (m, 4H), 7.73-7.83 (m, 2H), 8.27 (d, J=5.5Hz, 1H), 8.56 (s, 1H)

Example 30 Synthesis of3-((5-chloro-1-(3-(methylsulfonyl)propyl)-1H-indol-2-yl)methyl)-1-(4-chlorophenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one(P30)

Compound P30 was prepared by an analogous reaction protocol as describedfor compound P1 using intermediate 24-c and1-(4-chlorophenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one 41-c as startingmaterial.

m/z=529 (M+1)⁺

¹H NMR (360 MHz, DMSO-d₆) δ ppm 2.03 (m, J=7.7, 7.7 Hz, 2H), 2.94 (s,3H), 3.15 (m, J=15.7 Hz, 2H), 4.43 (t, J=7.5 Hz, 2H), 5.43 (s, 2H), 6.62(s, 1H), 7.10-7.23 (m, 2H), 7.52-7.61 (m, 2H), 7.67 (s, 4H), 8.26 (d,J=5.1 Hz, 1H), 8.56 (s, 1H)

Example 31 Synthesis of3-((5-chloro-1-(4-fluorobutyl)-1H-indol-2-yl)methyl)-1-(quinolin-6-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one(P31)

Compound P31 was prepared by an analogous reaction protocol as describedfor compound P1 using intermediate 28-a and1-(quinolin-6-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one 20-c as startingmaterial.

m/z=500 (M+1)⁺

¹H NMR (360 MHz, DMSO-d₆) δ ppm 1.52-1.78 (m, 4H), 4.26-4.41 (m, 3H),4.47 (t, J=5.5 Hz, 1H), 5.47 (s, 2H), 6.69 (s, 1H), 7.16 (dd, J=8.8, 2.2Hz, 1H), 7.28 (d, J=5.5 Hz, 1H), 7.54 (d, J=8.8 Hz, 1H), 7.60 (d, J=2.2Hz, 1H), 7.65 (dd, J=8.4, 4.4 Hz, 1H), 8.00 (dd, J=9.1, 2.2 Hz, 1H),8.19-8.33 (m, 3H), 8.51 (d, J=7.3 Hz, 1H), 8.58 (s, 1H), 9.02 (dd,J=4.2, 1.6 Hz, 1H)

Example 32 Synthesis of3-((5-chloro-1-(4-fluorobutyl)-1H-indol-2-yl)methyl)-1-(4-methoxy-phenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one(P32)

Compound P32 was prepared by an analogous reaction protocol as describedfor compound P1 using intermediate 28-a and1-(4-methoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one 22-c as startingmaterial.

m/z=479 (M+1)⁺

MP=163° C.

¹H NMR (360 MHz, DMSO-d₆) δ ppm 1.63 (m, J=2.9, 2.9 Hz, 4H), 3.84 (s,3H), 4.33 (m, J=5.5 Hz, 3H), 4.46 (t, J=5.9 Hz, 1H), 5.41 (s, 2H), 6.66(s, 1H), 6.99-7.04 (m, 1H), 7.10-7.19 (m, 3H), 7.44-7.55 (m, 3H), 7.59(d, J=2.2 Hz, 1H), 8.22 (d, J=5.5 Hz, 1H), 8.47-8.53 (m, 1H)

Example 33 Synthesis of4-(5-chloro-2-((1-(1-methyl-1H-imidazol-2-yl)-2-oxo-1H-imidazo[4,5-c]pyridin-3(2H)-yl)methyl)-1H-indol-1-yl)butanenitrile(P33)

Compound P33 was prepared by an analogous reaction protocol as describedfor compound P1 using intermediate 31-c and1-(1-methyl-1H-imidazol-2-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one 42-c asstarting material.

m/z=446 (M+1)⁺

Example 34 Synthesis of3-((5-chloro-1-(4-fluorobutyl)-1H-indol-2-yl)methyl)-1-(4-chlorophenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one(P34)

Compound P34 was prepared by an analogous reaction protocol as describedfor compound P1 using intermediate 28-a and1-(4-chlorophenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one 41-c as startingmaterial.

m/z=483 (M+1)⁺

MP=168° C.

¹H NMR (360 MHz, DMSO-d₆) δ ppm 1.53-1.72 (m, 4H), 4.32 (m, J=4.4 Hz,3H), 4.46 (t, J=5.5 Hz, 1H), 5.42 (s, 2H), 6.67 (s, 1H), 7.08-7.20 (m,2H), 7.52 (d, J=8.8 Hz, 1H), 7.59 (d, J=1.8 Hz, 1H), 7.61-7.73 (m, 4H),8.25 (d, J=5.5 Hz, 1H), 8.53 (s, 1H)

Example 35 Synthesis of3-((5-chloro-1-(3-(methylsulfonyl)propyl)-1H-indol-2-yl)methyl)-1-(4-methoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one(P35)

Compound P35 was prepared by an analogous reaction protocol as describedfor compound P1 using intermediate 24-c and1-(4-methoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one 22-c as startingmaterial.

m/z=525 (M+1)⁺

MP=215° C.

¹H NMR (360 MHz, DMSO-d₆) δ ppm 1.94-2.10 (m, 2H), 2.95 (s, 3H), 3.15(m, J=15.4 Hz, 2H), 3.84 (s, 3H), 4.43 (t, J=7.5 Hz, 2H), 5.43 (s, 2H),6.61 (s, 1H), 7.02 (d, J=5.1 Hz, 1H), 7.10-7.21 (m, 3H), 7.48-7.62 (m,4H), 8.23 (d, J=5.1 Hz, 1H), 8.53 (s, 1H)

Example 36 Synthesis of4-(5-chloro-2-((1-(1-methyl-1H-pyrazol-3-yl)-2-oxo-1H-imidazo[4,5-c]pyridin-3(2H)-yl)methyl)-1H-indol-1-yl)butanenitrile(P36)

Compound P36 was prepared by an analogous reaction protocol as describedfor compound P1 using intermediate 31-c and1-(1-methyl-1H-pyrazol-3-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one 44-c asstarting material.

m/z=446 (M+1)⁺

MP=244° C.

¹H NMR (360 MHz, DMSO-d₆) δ ppm 1.92 (quin, J=7.4 Hz, 2H), 2.56 (t,J=7.5 Hz, 2H), 3.93 (s, 3H), 4.35 (t, J=7.7 Hz, 2H), 5.44 (s, 2H), 6.46(s, 1H), 6.71 (d, J=2.2 Hz, 1H), 7.16 (dd, J=8.8, 2.2 Hz, 1H), 7.48-7.60(m, 2H), 7.78 (d, J=5.1 Hz, 1H), 7.88 (d, J=2.6 Hz, 1H), 8.34 (d, J=5.5Hz, 1H), 8.54 (s, 1H)

Example 37 Synthesis of4-(5-chloro-2-((1-(oxazol-2-yl)-2-oxo-1H-imidazo[4,5-c]pyridin-3(2H)-yl)methyl)-1H-indol-1-yl)butanenitrile(P37)

Compound P37 was prepared by an analogous reaction protocol as describedfor compound P1 using intermediate 31-c and1-(oxazol-2-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one 43-c as startingmaterial.

m/z=433 (M+1)⁺

MP=234° C.

¹H NMR (360 MHz, DMSO-d₆) δ ppm 1.89-2.07 (m, 2H), 2.58 (t, J=7.5 Hz,2H), 4.35 (m, J=15.4 Hz, 2H), 5.44 (s, 2H), 6.50 (s, 1H), 7.10-7.22 (m,1H), 7.47 (d, J=0.7 Hz, 1H), 7.51-7.60 (m, 2H), 7.74-7.82 (m, 1H), 8.26(d, J=1.1 Hz, 1H), 8.40 (d, J=5.1 Hz, 1H), 8.58 (s, 1H)

Example 38 Synthesis of3-((5-chloro-1-(4-fluorobutyl)-1H-indol-2-yl)methyl)-1-(1-methyl-1H-pyrazol-3-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one(P38)

Compound P38 was prepared by an analogous reaction protocol as describedfor compound P1 using intermediate 28-a and1-(1-methyl-1H-pyrazol-3-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one 44-c asstarting material.

m/z=453 (M+1)⁺

MP=169.3° C.

¹H NMR (360 MHz, DMSO-d₆) δ ppm 1.49-1.73 (m, 4H), 3.93 (s, 3H),4.25-4.35 (m, 3H), 4.42 (t, J=6.0 Hz, 1H), 5.42 (s, 2H), 6.59 (s, 1H),6.70 (d, J=2.2 Hz, 1H), 7.14 (dd, J=8.8, 2.2 Hz, 1H), 7.51 (d, J=8.8 Hz,1H), 7.58 (d, J=1.8 Hz, 1H), 7.77 (d, J=5.5 Hz, 1H), 7.88 (d, J=2.2 Hz,1H), 8.32 (d, J=5.5 Hz, 1H), 8.52 (s, 1H)

Example 39 Synthesis of4-(5-chloro-2-((1-(4-chlorophenyl)-2-oxo-1H-imidazo[4,5-c]pyridin-3(2H)-yl)methyl)-1H-indol-1-yl)butanenitrile(P39)

Compound P39 was prepared by an analogous reaction protocol as describedfor compound P1 using intermediate 31-c and1-(4-chlorophenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one 41-c as startingmaterial.

m/z=476 (M+1)⁺

MP=210.8° C.

¹H NMR (360 MHz, DMSO-d₆) δ ppm 1.88-2.05 (m, 2H), 2.52-2.61 (m, 2H),4.36 (t, J=7.9 Hz, 2H), 5.43 (s, 2H), 6.55 (s, 1H), 7.10-7.22 (m, 2H),7.49-7.60 (m, 2H), 7.63-7.72 (m, 4H), 8.26 (d, J=5.5 Hz, 1H), 8.55 (s,1H)

Example 40 Synthesis of4-(5-chloro-2-((6-fluoro-2-oxo-3-(pyridin-4-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)-1H-indol-1-yl)butanenitrile(P40)

Compound P40 was prepared by an analogous reaction protocol as describedfor compound P1 using intermediate 31-c and5-fluoro-1-(pyridin-4-yl)-1H-benzo[d]imidazol-2(3H)-one 38-c as startingmaterial.

m/z=461 (M+1)⁺

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.97 (quin, J=7.54 Hz, 2H) 2.56 (t,J=7.37 Hz, 2H) 4.20-4.41 (m, 2H) 5.39 (s, 2H) 6.44 (s, 1H) 6.91-7.01 (m,1H) 7.16 (dd, J=8.80, 2.20 Hz, 1H) 7.33-7.40 (m, 2H) 7.51-7.57 (m, 2H)7.68-7.77 (m, 2H) 8.67-8.83 (m, 2H)

Example 41 Synthesis of4-(5-chloro-2-((1-(4-(methylsulfonyl)phenyl)-2-oxo-1H-imidazo[4,5-c]pyridin-3(2H)-yl)methyl)-1H-indol-1-yl)butanenitrile(P41)

Compound P41 was prepared by an analogous reaction protocol as describedfor compound P1 using intermediate 31-c and1-(4-(methylsulfonyl)phenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one 50-c asstarting material.

m/z=521 (M+1)⁺

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.92-2.06 (m, 2H) 2.53-2.59 (m, 2H) 3.31(s, 3H) 4.36 (t, J=7.90 Hz, 2H) 5.45 (s, 2H) 6.56 (s, 1H) 7.09-7.22 (m,1H) 7.29 (d, J=5.28 Hz, 1H) 7.52-7.58 (m, 2H) 7.94 (d, J=8.58 Hz, 2H)8.16 (d, J=8.58 Hz, 2H) 8.30 (d, J=5.50 Hz, 1H) 8.57 (s, 1H)

Example 42 Synthesis of4-(5-chloro-2-((1-(3-fluoropyridin-4-yl)-2-oxo-1H-imidazo[4,5-c]pyridin-3(2H)-yl)methyl)-1H-indol-1-yl)butanenitrile(P42)

Compound P42 was prepared by an analogous reaction protocol as describedfor compound P1 using intermediate 31-c and1-(3-fluoropyridin-4-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one 36-c asstarting material.

m/z=462 (M+1)⁺

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.97 (quin, J=7.59 Hz, 2H) 2.52-2.57 (m,2H) 4.35 (t, J=7.59 Hz, 2H) 5.46 (s, 2H) 6.56 (s, 1H) 7.14-7.20 (m, 2H)7.55 (d, J=8.80 Hz, 1H) 7.58 (d, J=1.98 Hz, 1H) 7.81-7.88 (m, 1H) 8.31(d, J=5.50 Hz, 1H) 8.59 (s, 1H) 8.69 (d, J=5.06 Hz, 1H) 8.92 (d, J=1.98Hz, 1H)

Example 43 Synthesis of4-(5-chloro-2-((2-oxo-1-(quinolin-6-yl)-1H-imidazo[4,5-c]pyridin-3(2H)-yl)methyl)-1H-indol-1-yl)butanenitrile(P43)

Compound P43 was prepared by an analogous reaction protocol as describedfor compound P1 using intermediate 31-c and1-(quinolin-6-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one 20-c as startingmaterial.

m/z=494 (M+1)⁺

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.99 (quin, J=7.54 Hz, 2H) 2.57 (t,J=7.37 Hz, 2H) 4.19-4.51 (m, 2H) 5.48 (s, 2H) 6.59 (s, 1H) 7.18 (dd,J=8.80, 2.20 Hz, 1H) 7.28 (d, J=5.28 Hz, 1H) 7.56 (d, J=8.80 Hz, 1H)7.58 (d, J=1.98 Hz, 1H) 7.65 (dd, J=8.36, 4.18 Hz, 1H) 8.00 (dd, J=8.91,2.31 Hz, 1H) 8.24 (d, J=9.02 Hz, 1H) 8.27-8.31 (m, 2H) 8.50 (d, J=7.48Hz, 1H) 8.59 (s, 1H) 9.01 (dd, J=4.18, 1.54 Hz, 1H)

Example 44 Synthesis of3-((5-chloro-1-(4-fluorobutyl)-1H-indol-2-yl)methyl)-1-(pyridin-4-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one(P44)

Compound P44 was prepared by an analogous reaction protocol as describedfor compound P1 using intermediate 28-a and1-(pyridin-4-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one 20-c as startingmaterial.

m/z=451 (M+1)⁺

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.48-1.73 (m, 4H) 4.25-4.37 (m, 3H) 4.44(t, J=5.61 Hz, 1H) 5.43 (s, 2H) 6.66 (s, 1H) 7.15 (dd, J=8.69, 2.09 Hz,1H) 7.40 (dd, J=5.39, 0.55 Hz, 1H) 7.52 (d, J=8.80 Hz, 1H) 7.58 (d,J=1.98 Hz, 1H) 7.70-7.76 (m, 2H) 8.30 (d, J=5.28 Hz, 1H) 8.56 (s, 1H)8.77-8.83 (m, 2H)

Example 45 Synthesis of4-(5-chloro-2-((1-(2-fluoro-4-methoxyphenyl)-2-oxo-1H-imidazo[4,5-c]pyridin-3(2H)-yl)methyl)-1H-indol-1-yl)butanenitrile(P45)

Compound P45 was prepared by an analogous reaction protocol as describedfor compound P1 using intermediate 31-c and1-(2-fluoro-4-methoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one 46-c asstarting material.

m/z=491 (M+1)⁺

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.79-2.03 (m, 2H) 2.52-2.56 (m, 2H) 3.87(s, 3H) 4.22-4.45 (m, 2H) 5.41 (s, 2H) 6.51 (s, 1H) 6.91 (d, J=5.94 Hz,1H) 6.97-7.05 (m, 1H) 7.11-7.21 (m, 2H) 7.54 (d, J=9.02 Hz, 1H)7.57-7.63 (m, 2H) 8.23 (d, J=5.50 Hz, 1H) 8.53 (s, 1H)

Example 46 Synthesis of4-(5-chloro-2-((2-oxo-1-p-tolyl-1H-imidazo[4,5-c]pyridin-3(2H)-yl)methyl)-1H-indol-1-yl)butanenitrile(P46)

Compound P46 was prepared by an analogous reaction protocol as describedfor compound P1 using intermediate 31-c and1-p-tolyl-1H-imidazo[4,5-c]pyridin-2(3H)-one 51-c as starting material.

m/z=457 (M+1)⁺

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.94 (quin, J=7.54 Hz, 2H) 2.41 (s, 3H)2.52-2.58 (m, 2H) 4.23-4.45 (m, 2H) 5.43 (s, 2H) 6.55 (s, 1H) 7.07 (d,J=5.50 Hz, 1H) 7.16 (dd, J=8.69, 2.09 Hz, 1H) 7.37-7.50 (m, 4H) 7.54 (d,J=8.80 Hz, 1H) 7.57 (d, J=1.98 Hz, 1H) 8.24 (d, J=5.50 Hz, 1H) 8.52 (s,1H)

Example 47 Synthesis of4-(5-chloro-2-((1-(2,4-dimethoxyphenyl)-2-oxo-1H-imidazo[4,5-c]pyridin-3(2H)-yl)methyl)-1H-indol-1-yl)butanenitrile(P47)

Compound P47 was prepared by an analogous reaction protocol as describedfor compound P1 using intermediate 31-c and1-(2,4-dimethoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one 52-c asstarting material.

m/z=503 (M+1)⁺

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.74-2.06 (m, 2H) 3.35-3.42 (m, 2H) 3.73(s, 3H) 3.86 (s, 3H) 4.19-4.47 (m, 2H) 5.40 (s, 2H) 6.54 (s, 1H) 6.70(dd, J=8.80, 2.64 Hz, 1H) 6.73 (d, J=4.84 Hz, 1H) 6.82 (d, J=2.64 Hz,1H) 7.16 (dd, J=8.80, 1.98 Hz, 1H) 7.39 (d, J=8.58 Hz, 1H) 7.53 (d,J=8.80 Hz, 1H) 7.59 (d, J=2.20 Hz, 1H) 8.17 (d, J=5.28 Hz, 1H) 8.49 (s,1H)

Example 48 Synthesis of4-(5-chloro-2-((2-oxo-1-(pyridin-4-yl)-1H-imidazo[4,5-c]pyridin-3(2H)-yl)methyl)-1H-indol-1-yl)butanenitrile(P48)

Compound P48 was prepared by an analogous reaction protocol as describedfor compound P1 using intermediate 31-c and1-(pyridin-4-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one 34-c as startingmaterial.

m/z=444 (M+1)⁺

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.98 (quin, J=7.48 Hz, 2H) 2.56 (t,J=7.37 Hz, 2H) 4.27-4.42 (m, 2H) 5.45 (s, 2H) 6.54 (s, 1H) 7.17 (dd,J=8.69, 2.09 Hz, 1H) 7.41 (dd, J=5.39, 0.55 Hz, 1H) 7.51-7.59 (m, 2H)7.71-7.77 (m, 2H) 8.32 (d, J=5.50 Hz, 1H) 8.57 (s, 1H) 8.74-8.85 (m, 2H)

Example 49 Synthesis of4-(5-chloro-2-((2-oxo-1-(thiazol-2-yl)-1H-imidazo[4,5-c]pyridin-3(2H)-yl)methyl)-1H-indol-1-yl)butanenitrile(P49)

Compound P49 was prepared by an analogous reaction protocol as describedfor compound P1 using intermediate 31-c and1-(thiazol-2-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one 21-c as startingmaterial.

m/z=450 (M+1)⁺

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.98 (quin, J=7.59 Hz, 2H) 2.57 (t,J=7.37 Hz, 2H) 4.36 (t, J=7.59 Hz, 2H) 5.49 (s, 2H) 6.51 (s, 1H) 7.16(dd, J=8.69, 2.09 Hz, 1H) 7.49-7.58 (m, 2H) 7.63 (d, J=3.52 Hz, 1H) 7.79(d, J=3.52 Hz, 1H) 8.34 (d, J=5.28 Hz, 1H) 8.47 (d, J=5.28 Hz, 1H) 8.63(s, 1H)

Example 50 Synthesis of4-(3-((5-chloro-1-(3-cyanopropyl)-1H-indol-2-yl)methyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)benzonitrile(P50)

Compound P50 was prepared by an analogous reaction protocol as describedfor compound P1 using intermediate 31-c and4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)benzonitrile 47-c asstarting material.

m/z=468 (M+1)⁺

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.88-2.07 (m, 2H) 2.53-2.61 (m, 2H) 4.36(t, J=7.70 Hz, 2H) 5.44 (s, 2H) 6.56 (s, 1H) 7.17 (dd, J=8.80, 1.98 Hz,1H) 7.27 (d, J=5.28 Hz, 1H) 7.49-7.59 (m, 2H) 7.88 (d, J=8.58 Hz, 2H)8.09 (d, J=8.58 Hz, 2H) 8.29 (d, J=5.50 Hz, 1H) 8.56 (s, 1H)

Example 51 Synthesis of methyl4-(3-((5-chloro-1-(3-cyanopropyl)-1H-indol-2-yl)methyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)benzoate(P51)

Compound P51 was prepared by an analogous reaction protocol as describedfor compound P1 using intermediate 31-c and methyl4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)benzoate 48-c asstarting material.

m/z=501 (M+1)⁺

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.89-2.13 (m, 2H) 2.58 (t, J=7.37 Hz,2H) 3.92 (s, 3H) 4.26-4.43 (m, 2H) 5.50 (s, 2H) 6.58 (s, 1H) 7.18 (dd,J=8.69, 2.09 Hz, 1H) 7.50-7.60 (m, 3H) 7.78-7.87 (m, 2H) 8.17-8.25 (m,2H) 8.50 (d, J=6.16 Hz, 1H) 8.79 (s, 1H)

Example 52 Synthesis of4-(3-((5-chloro-1-(3-cyanopropyl)-1H-indol-2-yl)methyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)benzoicacid (P52)

Compound P51(650 mg, 1.17 mmol) was dissolved in 75 mL THF/Water (3:1)and a excess LiOH (112 mg, 4.68 mmol, 4 eq.) was added at roomtemperature. After two days stirring at room temperature the solutionwas adjusted till pH=6 with HCl (6M in water). The solid was filteredoff and further crystallized in MeOH/water to give the title compoundP52 (335 mg, 60%).

m/z=487 (M+1)⁺

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.87-2.04 (m, 2H) 2.53-2.59 (m, 2H)4.21-4.50 (m, 2H) 5.43 (s, 2H) 6.50 (s, 1H) 7.17 (dd, J=8.58, 1.98 Hz,1H) 7.25 (d, J=5.72 Hz, 1H) 7.44-7.62 (m, 2H) 7.77 (d, J=7.70 Hz, 2H)8.08-8.20 (m, 2H) 8.28 (d, J=5.50 Hz, 1H) 8.55 (s, 1H)

Example 53 Synthesis of4-(3-((5-chloro-1-(3-cyanopropyl)-1H-indol-2-yl)methyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)-N-cyclopropylbenzamide(P53)

To a solution of compound P52 (220 mg, 0.439 mmol) in 40 mL DMF, wasadded cyclopropylamine (0.092 mL, 1.32 mmol, 3 eq.), triethylamine(0.183 mL, 1.32 mmol, 3 eq.) and diethyl cyanophosphonate (0.2 mL, 1.32mmol, 3 eq.) at room temperature. After 16 hours the solution wasconcentrated in vacuo and taken up in diethyl ether.

The solid was filtered off and further crystallized in Diisopropylether/acetonitrile to yield the title compound P53 (160 mg, 68%) as awhite solid.

m/z=526 (M+1)⁺

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.49-0.66 (m, 2H) 0.69-0.77 (m, 2H)1.80-2.10 (m, 2H) 2.53-2.63 (m, 2H) 2.75-3.01 (m, 1H) 4.14-4.50 (m, 2H)5.44 (s, 2H) 6.55 (s, 1H) 7.12-7.20 (m, 2H) 7.55 (d, J=8.80 Hz, 1H) 7.57(d, J=1.98 Hz, 1H) 7.70 (d, J=8.58 Hz, 2H) 8.03 (d, J=8.80 Hz, 2H) 8.28(d, J=5.28 Hz, 1H) 8.55 (s, 1H) 8.58 (d, J=3.96 Hz, 1H)

Antiviral Activity

Black 96-well clear-bottom microtiter plates (Corning, Amsterdam, TheNetherlands) were filled in duplicate using a customized robot systemwith serial 4-fold dilutions of compound in a final volume of 50 μlculture medium [RPMI medium without phenol red, 10% FBS, 0.04%gentamycin (50 mg/ml) and 0.5% DMSO]. Then, 100 μl of a HeLa cellsuspension (5×10⁴ cells/ml) in culture medium was added to each wellfollowed by the addition of 50 μl rgRSV224 (MOI=0.02) virus in culturemedium using a multidrop dispenser (Thermo Scientific, Erembodegem,Belgium). rgRSV224 virus is an engineered virus that includes anadditional GFP gene (Hallak et al, 2000) and was in-licensed from theNIH (Bethesda, Md., USA). Medium, virus- and mock-infected controls wereincluded in each test. Cells were incubated at 37° C. in a 5% CO₂atmosphere. Three days post-virus exposure, viral replication wasquantified by measuring GFP expression in the cells by a MSM lasermicroscope (Tibotec, Beerse, Belgium). The EC₅₀ was defined as the 50%inhibitory concentration for GFP expression. In parallel, compounds wereincubated for three days in a set of white 96-well microtitier plates(Corning) and the cytotoxicity of compounds in HeLa cells was determinedby measuring the ATP content of the cells using the ATPlite kit(PerkinElmer, Zaventem, Belgium) according to the manufacturer'sinstructions. The CC50 was defined as the 50% concentration forcytotoxicity.

REFERENCES

-   Hallak L K, Spillmann D, Collins P L, Peeples M E. Glycosaminoglycan    sulfation requirements for respiratory syncytial virus infection. J.    Virol. 740, 10508-10513 (2000).

The following compounds were prepared according to the working examples.

WT activ- ity Tox Structure pEC₅₀ pCC₅₀ P1

8.3   4.3 P2

7.9   5.0 P3

7.0   4.9 P4

7.5 <4.0 P5

8.8   4.0 P6

8.4 <4.6 P7

9.3   4.3 P8

8.6   4.4 P9

9.0 <4.0 P10

n.d. n.d. P11

7.9 <4.6 P12

7.4   4.9 P13

n.d. n.d. P14

9.4   4.9 P15

9   <4   P16

9   <4.3 P17

8   <4   P18

8.7 <4   P19

9.9 <4   P20

9.4 <4   P21

8.2 <4   P22

8.4   4.6 P23

8.1 <4   P24

8   <4.3 P25

7.8 <4.3 P26

7.6 <4   P27

7.5 <4   P28

9.7 <4   P29

8.9 <4   P30

8.8 <4   P31

8.8 <4   P32

8.4   4.1 P33

8   <4   P34

7.5 <4   P35

9.5   4.5 P36

8.8   4.2 P37

8.8 <4   P38

8.8 <4   P39

8.4   4.6 P40

— <4   P41

9.7 <4   P42

9.5 <4   P43

9.4 <4   P44

9   <4   P45

9     4.8 P46

8.9 <4   P47

8.8 <4   P48

8.6 <4   P49

8.2 <4.6 P50

— — P51

9.1   4.4 P52

9.3 <4.6 P53

9.3   4.6

The following compounds can be prepared according to the workingexamples:

Composition Examples

“Active ingredient” (a.i.) as used throughout these examples relates toa compound of Formula (I), including any stereoisomeric form thereof, ora pharmaceutically acceptable addition salt or a solvate thereof; inparticular to any one of the exemplified compounds.

Typical examples of recipes for the formulation of the invention are asfollows:

1. Tablets

Active ingredient 5 to 50 mg Di-calcium phosphate 20 mg Lactose 30 mgTalcum 10 mg Magnesium stearate 5 mg Potato starch ad 200 mg

2. Suspension

An aqueous suspension is prepared for oral administration so that eachmilliliter contains 1 to 5 mg of active ingredient, 50 mg of sodiumcarboxymethyl cellulose, 1 mg of sodium benzoate, 500 mg of sorbitol andwater ad 1 ml.

3. Injectable

A parenteral composition is prepared by stirring 1.5% (weight/volume) ofactive ingredient in 0.9% NaCl solution or in 10% by volume propyleneglycol in water.

4. Ointment

Active ingredient 5 to 1000 mg Stearyl alcohol 3 g Lanoline 5 g Whitepetroleum 15 g Water ad 100 g

In this Example, active ingredient can be replaced with the same amountof any of the compounds according to the present invention, inparticular by the same amount of any of the exemplified compounds.

Reasonable variations are not to be regarded as a departure from thescope of the invention. It will be obvious that the thus describedinvention may be varied in many ways by those skilled in the art.

1. A compound of Formula (I),

or a stereoisomeric form thereof, wherein Het is a heterocycle havingformula (b), (c), (d) or (e):

each X independently is C or N; provided that at least one X is N;R^(1b) is present when Het has formula (b) and X is C; each R^(1b) isselected independently from the group consisting of H, halogen,C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, N(R⁶)₂, CO(R⁷), CH₂NH₂,CH₂OH, CN, C(═NOH)NH₂, C(═NOCH₃)NH₂, C(═NH)NH₂, CF₃, OCF₃, B(OH)₂ andB(O—C₁-C₆alkyl)₂; R^(1b) is absent when the X to which it is bound is N;R^(2b) is —(CR⁸R⁹)_(m)—R^(10b); each R⁶ is independently selected fromthe group consisting of H, COOCH₃ and CONHSO₂CH₃; each R⁷ isindependently selected from the group consisting of OH, C₁-C₆alkyloxy,NH₂, NHSO₂N(C₁-C₆alkyl)₂, NHSO₂NHCH₃, NHSO₂(C₁-C₆alkyl),NHSO₂(C₃-C₇cycloalkyl) and N(C₁-C₆-alkyl)₂; each R⁸ and R⁹ areindependently chosen from the group consisting of H, C₁-C₁₀alkyl andC₃-C₇cycloalkyl; or R⁸ and R⁹ taken together form a 4 to 6 memberedaliphatic ring that optionally contains one or more heteroatoms selectedfrom the group consisting of N, S and O; R^(10b) is selected from thegroup consisting of H, R¹¹, OH, CN, F, CF₂H, CF₃, CONR⁸R⁹, COOR⁸,CON(R⁸)SO₂R⁹, CON(R⁸)SO₂N(R⁸R⁹), NR⁸R⁹, NR⁸COOR⁹, OCOR⁸, O-Benzyl,NR⁸SO₂R⁹, SO₂NR⁸R⁹, SO₂R⁸, OCONR⁸R⁹, OCONR⁸R¹², N(R⁸)CON(R⁸R⁹),N(R⁸)COOR¹², and a 4 to 6 membered saturated ring containing one oxygenatom; m is an integer from 2 to 6; R¹¹ is selected from the groupconsisting of C₁-C₆ alkyl, C₃-C₇cycloalkyl, phenyl, pyridinyl andpyrazolyl; each optionally substituted with one or more substituentseach independently selected from the group consisting of CF₃, CH₃, OCH₃,OCF₃ and halogen; R¹² is selected from the group consisting of phenyl,pyridinyl and pyrazolyl; each optionally substituted with one or moresubstituents each independently selected from the group consisting ofCF₃, CH₃, OCH₃, OCF₃ and halogen;  or R¹² is C₁-C₆ alkyl orC₃-C₇cycloalkyl; each substituted with one or more substituents eachindependently selected from the group consisting of CF₃, CH₃, OCH₃, OCF₃and halogen; R^(1c) is present when Het has formula (c); each R^(1c) isselected independently from the group consisting of H, halogen,C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, N(R⁶)₂, CO(R^(7c)), CH₂NH₂,CH₂OH, CN, C(═NOH)NH₂, C(═NOCH₃)NH₂, C(═NH)NH₂, CF₃, OCF₃, B(OH)₂ andB(O—C₁-C₆alkyl)₂; R^(3c) is selected from the group consisting of H,halogen, C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy and CO(R^(7c));R^(2c) is —(CR⁸R⁹)_(m)—R^(10c); R^(7c) is selected from the groupconsisting of OH, O(C₁-C₆alkyl), NH₂, NHSO₂N(C₁-C₆alkyl)₂, NHSO₂NHCH₃,NHSO₂(C₁-C₆alkyl), NHSO₂(C₃-C₇cycloalkyl), N(C₁-C₆-alkyl)₂, NR⁸R⁹ andNR⁹R^(10c); R^(10c) is selected from the group consisting of H, R¹¹, OH,CN, F, CF₂H, CF₃, C(═NOH)NH₂, CONR⁸R⁹, COOR⁸, CONR⁸SO₂R⁹,CON(R⁸)SO₂N(R⁸R⁹), NR⁸R⁹, NR⁸COOR⁹, OCOR⁸, NR⁸SO₂R⁹, SO₂NR⁸R⁹, SO₂R⁸ anda 4 to 6 membered saturated ring containing one oxygen atom; R^(1d) ispresent when Het has formula (d) and X is C; each R^(1d) is selectedindependently from the group consisting of H, OH, halogen, C₁-C₆alkyl,C₃-C₇cycloalkyl, C₁-C₆alkyloxy, N(R⁶)₂, CO(R⁷), CH₂NH₂, CH₂OH,C(═NOH)NH₂, C(═NOCH₃)NH₂, C(═NH)NH₂, CF₃, OCF₃, B(OH)₂ andB(O—C₁-C₆alkyl)₂; R^(1d) is absent when the X to which it is bound is N;R^(3d) is selected from the group consisting of H, halogen, C₁-C₆alkyl,C₃-C₇cycloalkyl, C₁-C₆alkyloxy, and CO(R⁷); R^(2d) is—(CR⁸R⁹)_(m)—R^(10d); R^(10d) is selected from the group consisting ofH, R¹¹, OH, CN, F, CF₂H, CF₃, CONR⁸R⁹, COOR⁸, CONR⁸SO₂R⁹,CON(R⁸)SO₂N(R⁸R⁹), NR⁸R⁹, NR⁸COOR₉, OCOR⁸, NR⁸SO₂R⁹, SO₂NR⁸R⁹, SO₂R⁸ anda 4 to 6 membered saturated ring containing one oxygen atom; each Yindependently is C or N; R⁴ is selected from the group consisting oftert-butyl, Het¹, aryl, Het², CH(CH₃)(CF₃), and C₃-C₇cycloalkylsubstituted with one or more substituents selected from the groupconsisting of halo and C₁-C₄alkyl; aryl represents phenyl ornaphthalenyl; said aryl optionally being substituted with one or moresubstituents each independently selected from the group consisting ofhalo, C₁-C₄alkyloxy, C₁-C₄alkyl, OH, CN, CF₂H, CF₃, CF₃O, CONR⁸R⁹,COOR⁸, CON(R⁸)SO₂R⁹, CON(R⁸)SO₂N(R⁸R⁹), NR⁸R⁹, NR⁸COOR⁹, OCOR⁸,NR⁸SO₂R⁹, SO₂NR⁸R⁹, SO₂R⁸, OCONR⁸R⁹, OCONR⁸R¹², N(R⁸)CON(R⁸R⁹),N(R⁸)COOR¹² and C₁₋₄alkyloxyC₁₋₄alkyloxy; Het¹ represents a 4 to 6membered saturated ring containing one N atom, optionally beingsubstituted with one or more substituents each independently selectedfrom the group consisting of halo, C₁-C₄alkyloxy, SO₂R⁸,C₁-C₄alkylcarbonyl, CO(aryl), COHet², C₁-C₄alkyloxycarbonyl, pyridinyl,CF₃, SO₂N(C₁-C₄alkyl)₂, SO₂NH(C₁-C₄alkyl), (C═O)NH(C₁₋₄alkyl),(C═S)NH(C₁₋₄alkyl), C₁-C₄alkyl and C₁-C₄alkyl substituted with onehydroxy; or  Het¹ represents a 4 to 6 membered saturated ring containingone O atom, substituted with one or more substituents each independentlyselected from the group consisting of halo, C₁-C₄alkyloxy, CF₃,NH(C═O)(C₁₋₄alkyl), (C═O)NH(C₁₋₄alkyl) and C₁-C₄alkyl; or  Het¹represents a bicyclic 7 to 11 membered non-aromatic heterocyclecontaining one or two heteroatoms each independently selected from thegroup consisting of O, S and N, optionally substituted with one or moresubstituents each independently selected from the group consisting ofhalo, C₁-C₄alkyloxy, SO₂R⁸, C₁-C₄alkylcarbonyl, CO(aryl), COHet²,C₁-C₄alkyloxycarbonyl, pyridinyl, CF₃, SO₂N(C₁-C₄alkyl)₂,SO₂NH(C₁-C₄alkyl), (C═O)NH(C₁₋₄alkyl), (C═S)NH(C₁₋₄alkyl), C₁-C₄alkyland C₁-C₄alkyl substituted with one hydroxy; Het² represents amonocyclic 5 to 6 membered aromatic heterocycle containing one or moreheteroatoms each independently selected from the group consisting of O,S and N; or a bicyclic 8 to 12 membered aromatic heterocycle containingone or more heteroatoms each independently selected from the groupconsisting of O, S and N; said Het² optionally being substituted withone or more substituents each independently selected from the groupconsisting of halo, C₁-C₄alkyloxy, C₁-C₄alkyl, OH, CN, CF₂H, CF₃,CONR⁸R⁹, COOR⁸, CON(R⁸)SO₂R⁹, CON(R⁸)SO₂N(R⁸R⁹), NR⁸R⁹, NR⁸COOR⁹, OCOR⁸,NR⁸SO₂R⁹, SO₂NR⁸R⁹, SO₂R⁸, OCONR⁸R⁹, OCONR⁸R¹², N(R⁸)CON(R⁸R⁹), andN(R⁸)COOR¹²; Z is C or N; R⁵ is present where Z is C, whereby R⁵ isselected form the group consisting of hydrogen, CF₃ and halogen; R⁵ isabsent where Z is N; or a pharmaceutically acceptable addition salt or asolvate thereof.
 2. The compound according to claim 1, wherein Het is aheterocycle having formula (b), (c), or (d); each X independently is Cor N; provided that at least one X is N; R^(1b) is present when Het hasformula (b) and X is C; each R^(1b) is selected independently from thegroup consisting of H, halogen, C₁-C₆alkyl, C₃-C₇cycloalkyl,C₁-C₆alkyloxy, CF₃ and OCF₃; R^(1b) is absent when the X to which it isbound is N; R^(2b) is —(CR⁸R⁹)_(m)—R^(10b); each R⁸ and R⁹ areindependently chosen from the group consisting of H and C₁-C₁₀alkyl;R^(10b) is selected from the group consisting of H, R¹¹, OH, CN, F,CF₂H, CF₃, NR⁸R⁹, SO₂NR⁸R⁹ and SO₂R⁸; m is an integer from 2 to 6; R¹¹is selected from the group consisting of C₁-C₆ alkyl, C₃-C₇cycloalkyl,phenyl, pyridinyl and pyrazolyl; each optionally substituted with one ormore substituents each independently selected from the group consistingof CF₃, CH₃, OCH₃, OCF₃ and halogen; R¹² is selected from the groupconsisting of phenyl, pyridinyl and pyrazolyl; each optionallysubstituted with one or more substituents each independently selectedfrom the group consisting of CF₃, CH₃, OCH₃, OCF₃ and halogen;  or R¹²is C₁-C₆ alkyl or C₃-C₇cycloalkyl; each substituted with one or moresubstituents each independently selected from the group consisting ofCF₃, CH₃, OCH₃, OCF₃ and halogen; R^(1c) is present when Het has formula(c); each R^(1c) is selected independently from the group consisting ofH, halogen, C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, CF₃ and OCF₃;R^(3c) is selected from the group consisting of H, halogen andC₁-C₆alkyl; R^(2c) is —(CR⁸R⁹)_(m)—R^(10c); R^(10c) is selected from thegroup consisting of H, C₁-C₆alkyl, OH, CN, F, CF₂H, CF₃, NR⁸R⁹, SO₂NR⁸R⁹and SO₂R⁸; R^(1d) is present when Het has formula (d) and X is C; eachR^(1d) is selected independently from the group consisting of H,halogen, C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆alkyloxy, CF₃ and OCF₃;R^(1d) is absent when the X to which it is bound is N; R^(3d) isselected from the group consisting of H, halogen and C₁-C₆alkyl; R^(2d)is —(CR⁸R⁹)_(m)—R^(10d); R^(10d) is selected from the group consistingof H, C₁-C₆alkyl, OH, CN, F, CF₂H, CF₃, NR⁸R⁹, SO₂NR⁸R⁹ and SO₂R⁸; eachY independently is C or N; R⁴ is selected from the group consisting oftert-butyl, Het¹, aryl, Het², CH(CH₃)(CF₃), and C₃-C₇cycloalkylsubstituted with one or more substituents selected from the groupconsisting of halo and C₁-C₄alkyl; aryl represents phenyl ornaphthalenyl; said aryl optionally being substituted with one or moresubstituents each independently selected from the group consisting ofhalo, C₁-C₄alkyloxy, C₁-C₄alkyl, OH, CN, CF₂H, CF₃, CONR⁸R⁹, NR⁸R⁹,NR⁸COOR⁹, SO₂NR⁸R⁹, SO₂R⁸, OCONR⁸R⁹, OCONR⁸R¹² and N(R⁸)COOR¹²; Het¹represents a 4 to 6 membered saturated ring containing one N atom,optionally being substituted with one or more substituents eachindependently selected from the group consisting of halo, C₁-C₄alkyloxy,CF₃, SO₂R⁸, C₁-C₄alkylcarbonyl, C₁-C₄alkyloxycarbonyl, pyridinyl,SO₂N(C₁-C₄alkyl)₂, SO₂NH(C₁-C₄alkyl), (C═O)NH(C₁-4alkyl),(C═S)NH(C₁₋₄alkyl), C₁-C₄alkyl and C₁-C₄alkyl substituted with onehydroxy; or Het¹ represents a 4 to 6 membered saturated ring containingone O atom, substituted with one or more substituents each independentlyselected from the group consisting of halo, C₁-C₄alkyloxy, CF₃,NH(C═O)(C₁₋₄alkyl), (C═O)NH(C₁₋₄alkyl) and C₁-C₄alkyl; Het² represents amonocyclic 5 to 6 membered aromatic heterocycle containing one or moreheteroatoms each independently selected from the group consisting of O,S and N; or a bicyclic 8 to 12 membered aromatic heterocycle containingone or more heteroatoms each independently selected from the groupconsisting of O, S and N; said Het² optionally being substituted withone or more substituents each independently selected from the groupconsisting of halo, C₁-C₄alkyloxy, C₁-C₄alkyl, OH, CN, CF₂H, CF₃,CONR⁸R⁹, NR⁸R⁹, NR⁸COOR⁹, SO₂NR⁸R⁹, SO₂R⁸, OCONR⁸R⁹, OCONR⁸R¹² andN(R⁸)COOR¹²; Z is C or N; R⁵ is present where Z is C, whereby R⁵ isselected form the group consisting of hydrogen, CF₃ and halogen; R⁵ isabsent where Z is N; and the pharmaceutically acceptable addition salts,and the solvates thereof.
 3. The compound according to claim 1, whereinHet is a heterocycle having formula (b) or (d).
 4. The compoundaccording to claim 1, wherein Het is a heterocycle having formula (c).5. The compound according to claim 1, wherein Z is N and R⁵ is absent.6. The compound according to claim 1, wherein Z is C and R⁵ is halogen.7. The compound according to claim 1, wherein R⁴ is selected from thegroup consisting of Het¹, aryl, Het², and C₃-C₇cycloalkyl substitutedwith one or more substituents selected from the group consisting of haloand C₁-C₄alkyl.
 8. The compound according to claim 7 wherein R⁴ is Het¹.9. The compound according to claim 7 wherein R⁴ is Het².
 10. Thecompound according to claim 7 wherein R⁴ is aryl.
 11. The compoundaccording to claim 10 wherein aryl is phenyl optionally beingsubstituted with one or more substituents each independently selectedfrom the group consisting of halo, C₁-C₄alkyloxy, C₁-C₄alkyl, CN,CONR⁸R⁹, COOR⁸ and SO₂R⁸.
 12. The compound according to claim 11 whereinaryl is phenyl substituted with two substituents each independentlyselected from the group consisting of halo, C₁-C₄alkyloxy andC₁-C₄alkyl.
 13. The compound according to claim 12 wherein Het is offormula (c-1a)

wherein R^(3c) is H and R^(2c) is —(CR⁸R⁹)_(m)—R^(10c); wherein R⁸ andR⁹ are each H; m is 3; and R^(10c) represents CN or SO₂CH₃.
 14. Thecompound according to claim 1 wherein aryl is phenyl optionally beingsubstituted with one or more substituents each independently selectedfrom the group consisting of halo, C₁-C₄alkyloxy, C₁-C₄alkyl, CN,CONR⁸R⁹, COOR⁸, SO₂R⁸, CF₃O and C₁₋₄alkyloxyC₁₋₄alkyloxy.
 15. Thecompound according to claim 1 wherein the compound is


16. (canceled)
 17. A pharmaceutical composition comprising apharmaceutically acceptable carrier, and as active ingredient atherapeutically effective amount of a compound as defined in claim 1.18. (canceled)
 19. A method of treating a respiratory syncytial viral(RSV) infection comprising administering to a subject in need oftreatment an anti-virally effective amount of a compound as claimed inclaim
 1. 20. A compound selected from the group consisting of:tert-Butyl-3-(3-((5-chloro-1-(3-(methyl-sulfonyl)propyl)-1H-indol-2-yl)methyl)-2-oxo-2;3-dihydro-1H-imidazo[4;5-c]pyridin-1-yl)azetidine-1-carboxylate;tert-Butyl3-(3-((5-chloro-1-(3-(methylsulfonyl)propyl)-1H-indol-2-yl)methyl)-5-fluoro-2-oxo-2;3-dihydro-1H-benzo[d]imidazol-1-yl)azetidine-1-carboxylate;1-(Azetidin-3-yl)-3-((5-chloro-1-(3-(methylsulfonyl)propyl)-1H-indol-2-yl)methyl)-5-fluoro-1H-benzo[d]imidazol-2(3H)-one;1-(Azetidin-3-yl)-3-((5-chloro-1-(3-(methylsulfonyl)propyl)-1H-indol-2-yl)methyl)-1H-imidazo[4;5-c]pyridin-2(3H)-one;3-((5-Chloro-1-(3-(methylsulfonyl)propyl)-1H-indol-2-yl)methyl)-1-(1-(methylsulfonyl)azetidin-3-yl)-1H-imidazo[4;5-c]pyridin-2(3H)-one;1-(1-Acetylazetidin-3-yl)-3-((5-chloro-1-(3-(methylsulfonyl)propyl)-1H-indol-2-yl)methyl)-1H-imidazo[4;5-c]pyridin-2(3H)-one;3-((5-Chloro-1-(3-(methylsulfonyl)propyl)-1H-indol-2-yl)methyl)-1-(1-methylcyclopropyl)-1H-imidazo[4;5-c]pyridin-2(3H)-one;1-tert-Butyl-3-((5-chloro-1-(3-(methylsulfonyl)propyl)-1H-indol-2-yl)methyl)-1H-imidazo[4;5-c]pyridin-2(3H)-one;3-((5-Chloro-1-(4;4;4-trifluorobutyl)-1H-imidazo[4;5-b]pyridin-2-yl)-methyl)-1-(1-methylcyclopropyl)-1H-imidazo[4;5-c]pyridin-2(3H)-one;3-((5-Chloro-1-(4-fluorobutyl)-1H-imidazo[4;5-b]pyridin-2-yl)methyl)-1-(thiazol-2-yl)-1H-imidazo[4;5-c]pyridin-2(3H)-one;3-((5-Chloro-1-(4-fluorobutyl)-1H-indol-2-yl)methyl)-1-(thiazol-2-yl)-1H-imidazo[4;5-c]pyridin-2(3H)-one;3-((5-Chloro-1-(3(methylsulfonyl)propyl)-1H-indol-2-yl)methyl)-5-fluoro-1-(1-(2-hydroxy-2-methylpropyl)azetidin-3-yl)-1H-benzo[d]imidazol-2(3H)-one;3-((5-Chloro-1-isopentyl-1H-imidazo[4;5-b]pyridin-2-yl)methyl)-1-(quinolin-6-yl)-1H-imidazo[4;5-c]pyridin-2(3H)-one;4-(5-Chloro-2-((1-(4-methoxyphenyl)-2-oxo-1H-imidazo[4;5-c]pyridin-3(2H)-yl)methyl)-1H-indol-1-yl)butanenitrile;4-(5-Chloro-2-((1-(3-fluoro-4-methoxyphenyl)-2-oxo-1H-imidazo[4;5-c]pyridin-3(2H)-yl)methyl)-1H-indol-1-yl)butanenitrile;3-((5-Chloro-1-isopentyl-1H-imidazo[4;5-b]pyridin-2-yl)methyl)-1-(4-methoxyphenyl)-1H-imidazo[4;5-c]pyridin-2(3H)-one;3-((5-Chloro-1-(4;4;4-trifluorobutyl)-1H-pyrrolo[3;2-b]pyridin-2-yl)-methyl)-1-(4-methoxyphenyl)-1H-imidazo[4;5-c]pyridin-2(3H)-one;3-((5-Chloro-1-isopentyl-1H-imidazo[4;5-b]pyridin-2-yl)methyl)-1-(1-methylcyclopropyl)-1H-imidazo[4;5-c]pyridin-2(3H)-one;4-(5-Chloro-2-((1-(3;4-dimethoxyphenyl)-2-oxo-1H-imidazo[4;5-c]pyridin-3(2H)-yl)methyl)-1H-indol-1-yl)butanenitrile;4-(5-Chloro-2-((1-(4-methoxy-2-methylphenyl)-2-oxo-1H-imidazo[4;5-c]pyridin-3(2H)-yl)methyl)-1H-indol-1-yl)butanenitrile;4-(5-Chloro-2-((2-oxo-1-(pyrimidin-2-yl)-1H-imidazo[4;5-c]pyridin-3(2H)-yl)methyl)-1H-indol-1-yl)butanenitrile;3-((5-Chloro-1-isopentyl-1H-imidazo[4;5-b]pyridin-2-yl)methyl)-1-(thiazol-2-yl)-1H-imidazo[4;5-c]pyridin-2(3H)-one;3-((5-Chloro-1-isopentyl-1H-imidazo[4;5-b]pyridin-2-yl)methyl)-1-(pyridin-4-yl)-1H-imidazo[4;5-c]pyridin-2(3H)-one;4-(5-Chloro-2-((2-oxo-1-(pyrimidin-4-yl)-1H-imidazo[4;5-c]pyridin-3(2H)-yl)methyl)-1H-indol-1-yl)butanenitrile;3-((5-Chloro-1-isopentyl-1H-imidazo[4;5-b]pyridin-2-yl)methyl)-5-fluoro-1-(thiazol-2-yl)-1H-benzo[d]imidazol-2(3H)-one;3-((5-Chloro-1-isopentyl-1H-imidazo[4;5-b]pyridin-2-yl)methyl)-1-(3-fluoropyridin-4-yl)-1H-imidazo[4;5-c]pyridin-2(3H)-one;4-(5-Chloro-2-((6-fluoro-2-oxo-3-(thiazol-2-yl)-2;3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)-1H-indol-1-yl)butanenitrile;4-(5-Chloro-2-((1-(4-(2-methoxyethoxy)phenyl)-2-oxo-1H-imidazo[4;5-c]pyridin-3(2H)-yl)methyl)-1H-indol-1-yl)butanenitrile;4-(5-Chloro-2-((2-oxo-1-(4-(trifluoromethoxy)phenyl)-1H-imidazo[4;5-c]pyridin-3(2H)-yl)methyl)-1H-indol-1-yl)butanenitrile;3-((5-Chloro-1-(3-(methylsulfonyl)propyl)-1H-indol-2-yl)methyl)-1-(4-chlorophenyl)-1H-imidazo[4;5-c]pyridin-2(3H)-one;3-((5-Chloro-1-(4-fluorobutyl)-1H-indol-2-yl)methyl)-1-(quinolin-6-yl)-1H-imidazo[4;5-c]pyridin-2(3H)-one;3-((5-Chloro-1-(4-fluorobutyl)-1H-indol-2-yl)methyl)-1-(4-methoxy-phenyl)-1H-imidazo[4;5-c]pyridin-2(3H)-one;4-(5-Chloro-2-((1-(1-methyl-1H-imidazol-2-yl)-2-oxo-1H-imidazo[4;5-c]pyridin-3(2H)-yl)methyl)-1H-indol-1-yl)butanenitrile;3-((5-Chloro-1-(4-fluorobutyl)-1H-indol-2-yl)methyl)-1-(4-chlorophenyl)-1H-imidazo[4;5-c]pyridin-2(3H)-one;3-((5-Chloro-1-(3-(methylsulfonyl)propyl)-1H-indol-2-yl)methyl)-1-(4-methoxyphenyl)-1H-imidazo[4;5-c]pyridin-2(3H)-one;4-(5-Chloro-2-((1-(1-methyl-1H-pyrazol-3-yl)-2-oxo-1H-imidazo[4;5-c]pyridin-3(2H)-yl)methyl)-1H-indol-1-yl)butanenitrile;4-(5-Chloro-2-((1-(oxazol-2-yl)-2-oxo-1H-imidazo[4;5-c]pyridin-3(2H)-yl)methyl)-1H-indol-1-yl)butanenitrile;3-((5-Chloro-1-(4-fluorobutyl)-1H-indol-2-yl)methyl)-1-(1-methyl-1H-pyrazol-3-yl)-1H-imidazo[4;5-c]pyridin-2(3H)-one;4-(5-Chloro-2-((1-(4-chlorophenyl)-2-oxo-1H-imidazo[4;5-c]pyridin-3(2H)-yl)methyl)-1H-indol-1-yl)butanenitrile;4-(5-Chloro-2-((6-fluoro-2-oxo-3-(pyridin-4-yl)-2;3-dihydro-1H-benzo[d]imidazol-1-yl)methyl)-1H-indol-1-yl)butanenitrile;4-(5-Chloro-2-((1-(4-(methylsulfonyl)phenyl)-2-oxo-1H-imidazo[4;5-c]pyridin-3(2H)-yl)methyl)-1H-indol-1-yl)butanenitrile;4-(5-Chloro-2-((1-(3-fluoropyridin-4-yl)-2-oxo-1H-imidazo[4;5-c]pyridin-3(2H)-yl)methyl)-1H-indol-1-yl)butanenitrile;4-(5-Chloro-2-((2-oxo-1-(quinolin-6-yl)-1H-imidazo[4;5-c]pyridin-3(2H)-yl)methyl)-1H-indol-1-yl)butanenitrile;3-((5-Chloro-1-(4-fluorobutyl)-1H-indol-2-yl)methyl)-1-(pyridin-4-yl)-1H-imidazo[4;5-c]pyridin-2(3H)-one;4-(5-Chloro-2-((1-(2-fluoro-4-methoxyphenyl)-2-oxo-1H-imidazo[4;5-c]pyridin-3(2H)-yl)methyl)-1H-indol-1-yl)butanenitrile;4-(5-Chloro-2-((2-oxo-1-p-tolyl-1H-imidazo[4;5-c]pyridin-3(2H)-yl)methyl)-1H-indol-1-yl)butanenitrile;4-(5-Chloro-2-((1-(2;4-dimethoxyphenyl)-2-oxo-1H-imidazo[4;5-c]pyridin-3(2H)-yl)methyl)-1H-indol-1-yl)butanenitrile;4-(5-Chloro-2-((2-oxo-1-(pyridin-4-yl)-1H-imidazo[4;5-c]pyridin-3(2H)-yl)methyl)-1H-indol-1-yl)butanenitrile;4-(5-Chloro-2-((2-oxo-1-(thiazol-2-yl)-1H-imidazo[4;5-c]pyridin-3(2H)-yl)methyl)-1H-indol-1-yl)butanenitrile;4-(3-((5-Chloro-1-(3-cyanopropyl)-1H-indol-2-yl)methyl)-2-oxo-2;3-dihydro-1H-imidazo[4;5-c]pyridin-1-yl)benzonitrile;Methyl4-(3-((5-chloro-1-(3-cyanopropyl)-1H-indol-2-yl)methyl)-2-oxo-2;3-dihydro-1H-imidazo[4;5-c]pyridin-1-yl)benzoate;4-(3-((5-Chloro-1-(3-cyanopropyl)-1H-indol-2-yl)methyl)-2-oxo-2;3-dihydro-1H-imidazo[4;5-c]pyridin-1-yl)benzoicacid;4-(3-((5-Chloro-1-(3-cyanopropyl)-1H-indol-2-yl)methyl)-2-oxo-2;3-dihydro-1H-imidazo[4;5-c]pyridin-1-yl)-N-cyclopropylbenzamide;4-[5-Chloro-2-[[1-(4-methoxy-3-methyl-phenyl)-2-oxo-imidazo[4;5-c]pyridin-3-yl]methyl]indol-1-yl]butanenitrile;3-[[5-Chloro-1-(3-methylsulfonylpropyl)indol-2-yl]methyl]-1-(4-methoxy-3-methyl-phenyl)imidazo[4;5-c]pyridin-2-one;3-[[5-Chloro-1-(3-methylsulfonylpropyl)indol-2-yl]methyl]-1-(3;4-dimethoxyphenyl)imidazo[4;5-c]pyridin-2-one;and pharmaceutically acceptable addition salts and solvates thereof.